Aromatic sulfone hydroxamic acids and their use as protease inhibitors

ABSTRACT

This invention is directed to aromatic sulfone hydroxamates (also known as aromatic sulfone hydroxamic acids) and salts thereof that, inter alia, tend to inhibit matrix metalloproteinase (also known as matrix metalloprotease or MMP) activity and/or aggrecanase activity. This invention also is directed to a treatment method that comprises administering such a compound or salt in an MMP-inhibiting and/or aggrecanase-inhibiting effective amount to an animal, particularly a mammal having (or disposed to having) a pathological condition associated with MMP activity and/or aggrecanase activity.

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

[0001] This patent claims priority as a continuation-in-part to U.S.patent application Ser. No. 09/570,731 (filed May 12, 2000), which, inturn, claims priority to U.S. patent application Ser. No. 09/311,837(filed May 14, 1999) and Ser. No. 09/256,948 (filed Feb. 24, 1999),which, in turn, claim priority to U.S. patent application Ser. No.09/191,129 (filed Nov. 13, 1998), Ser. No. 09/186,410 (filed Nov. 5,1998), 60/066,007 (filed Nov. 14, 1997), 60/095,347 (filed Aug. 4,1998), 60/095,501 (filed Aug. 6, 1998), and 60/101,080 (filed Sep. 18,1998). The entire texts of the above-referenced patent applications areincorporated by reference into this patent.

FIELD OF THE INVENTION

[0002] This invention is directed generally to proteinase (also known as“protease”) inhibitors, and, more particularly, to aromatic sulfonehydroxamate compounds (also known as “aromatic sulfone hydroxamic acidcompounds”) and salts thereof (particularly pharmaceutically acceptablesalts) that, inter alia, inhibit matrix metalloproteinase (also known as“matrix metalloprotease” or “MMP”) and/or aggrecanase activity. Thisinvention also is directed to pharmaceutical compositions of suchcompounds and salts, and methods of using such compounds and salts toprevent or treat conditions associated with MMP and/or aggrecanaseactivity, particularly pathological conditions.

BACKGROUND OF THE INVENTION

[0003] Connective tissue is a required component of all mammals. Itprovides rigidity, differentiation, attachments, and, in some cases,elasticity. Connective tissue components include, for example, collagen,elastin, proteoglycans, fibronectin, and laminin. These biochemicalsmake up (or are components of) structures, such as skin, bone, teeth,tendon, cartilage, basement membrane, blood vessels, cornea, andvitreous humor.

[0004] Under normal conditions, connective tissue turnover and/or repairprocesses are in equilibrium with connective tissue production.Degradation of connective tissue is carried out by the action ofproteinases released from resident tissue cells and/or invadinginflammatory or tumor cells.

[0005] Matrix metalloproteinases, a family of zinc-dependentproteinases, make up a major class of enzymes involved in degradingconnective tissue. Matrix metalloproteinases are divided into classes,with some members having several different names in common use. Examplesare: MMP-1 (also known as collagenase 1, fibroblast collagenase, or EC3.4.24.3); MMP-2 (also known as gelatinase A, 72 kDa gelatinase,basement membrane collagenase, or EC 3.4.24.24), MMP-3 (also known asstromelysin 1 or EC 3.4.24.17), proteoglycanase, MMP-7 (also known asmatrilysin), MMP-8 (also known as collagenase II, neutrophilcollagenase, or EC 3.4.24.34), MMP-9 (also known as gelatinase B, 92 kDagelatinase, or EC 3.4.24.35), MMP-10 (also known as stromelysin 2 or EC3.4.24.22), MMP-1 I (also known as stromelysin 3), MMP-12 (also known asmetalloelastase, human macrophage elastase or HME), MMP-13 (also knownas collagenase 111), and MMP-14 (also known as MT1-MMP or membrane MMP).See, generally, Woessner, J. F., “The Matrix Metalloprotease Family” inMatrix Metalloproteinases, pp.1-14 (Edited by Parks, W. C. & Mecham, R.P., Academic Press, San Diego, Calif. 1998).

[0006] Excessive breakdown of connective tissue by MMPs is a feature ofmany pathological conditions. Inhibition of MMPs therefore provides acontrol mechanism for tissue decomposition to prevent and/or treat thesepathological conditions. Such pathological conditions generally include,for example, tissue destruction, fibrotic diseases, pathological matrixweakening, defective injury repair, cardiovascular diseases, pulmonarydiseases, kidney diseases, liver diseases, and diseases of the centralnervous system. Specific examples of such conditions include, forexample, rheumatoid arthritis, osteoarthritis, septic arthritis,multiple sclerosis, a decubitis ulcer, corneal ulceration, epidermalulceration, gastric ulceration, tumor metastasis, tumor invasion, tumorangiogenesis, periodontal disease, liver cirrhosis, fibrotic lungdisease, emphysema, otosclerosis, atherosclerosis, proteinuria, coronarythrombosis, dilated cardiomyopathy, congestive heart failure, aorticaneurysm, epidermolysis bullosa, bone disease, Alzheimer's disease, anddefective injury repair (e.g., weak repairs, adhesions such aspost-surgical adhesions, and scarring).

[0007] Matrix metalloproteinases also are involved in the biosynthesisof tumor necrosis factors (TNFs). Tumor necrosis factors are implicatedin many pathological conditions. TNF-α, for example, is a cytokine thatis presently thought to be produced initially as a 28 kD cell-associatedmolecule. It is released as an active, 17 kD form that can mediate alarge number of deleterious effects in vitro and in vivo. TNF-α cancause and/or contribute to the effects of inflammation (e.g. rheumatoidarthritis), autoimmune disease, graft rejection, multiple sclerosis,fibrotic diseases, cancer, infectious diseases (e.g., malaria,mycobacterial infection, meningitis, etc.), fever, psoriasis,cardiovascular diseases (e.g., post-ischemic reperfusion injury andcongestive heart failure), pulmonary diseases, hemorrhage, coagulation,hyperoxic alveolar injury, radiation damage, and acute phase responseslike those seen with infections and sepsis and during shock (e.g.,septic shock and hemodynamic shock). Chronic release of active TNF-α cancause cachexia and anorexia. TNF-α also can be lethal.

[0008] Inhibiting TNF (and related compounds) production and action isan important clinical disease treatment. Matrix metalloproteinaseinhibition is one mechanism that can be used. MMP (e.g., collagenase,stromelysin, and gelatinase) inhibitors, for example, have been reportedto inhibit TNF-α release. See, e.g., Gearing et al. Nature 376, 555-557(1994). See also, McGeehan et al. See also, Nature 376, 558-561 (1994).MMP inhibitors also have been reported to inhibit TNF-α convertase, ametalloproteinase involved in forming active TNF-α. See, e.g., WIPOInt'l Pub. No. WO 94/24140. See also, WIPO Int'l Pub. No. WO 94/02466.See also, WIPO Int'l Pub. No. WO 97/20824.

[0009] Matrix metalloproteinases also are involved in other biochemicalprocesses in mammals. These include control of ovulation, postpartumuterine involution, possibly implantation, cleavage of APP (β-amyloidprecursor protein) to the ainyloid plaque, and inactivation of(α₁-protease inhibitor (α₁-PI). Inhibiting MMPs therefore may be amechanism that may be used to control of fertility. In addition,increasing and maintaining the levels of an endogenous or administeredserine protease inhibitor (e.g., α₁-PI) supports the treatment andprevention of pathological conditions such as emphysema, pulmonarydiseases, inflammatory diseases, and diseases of aging (e.g., loss ofskin or organ stretch and resiliency).

[0010] Numerous metalloproteinase inhibitors are known. See, generally,Brown, P. D., “Synthetic Inhibitors of Matrix Metalloproteinases,” inMatrix Metalloproteinases, pp. 243-61 (Edited by Parks, W. C. & Mecham,R. P., Academic Press, San Diego, Calif. 1998).

[0011] Metalloproteinase inhibitors include, for example, naturalbiochemicals, such as tissue inhibitor of metalloproteinase (TIMP),α2-macroglobulin, and their analogs and derivatives. These arehigh-molecular-weight protein molecules that form inactive complexeswith metalloproteinases.

[0012] A number of smaller peptide-like compounds also have beenreported to inhibit metalloproteinases. Mercaptoamide peptidylderivatives, for example, have been reported to inhibit angiotensinconiierting enzyme (also known as ACE) in vitro and in vivo. ACE aids inthe production of angiotensin II, a potent pressor substance in mammals.Inhibiting ACE leads to lowering of blood pressure.

[0013] A wide variety of thiol compounds have been reported to inhibitMMPs. See, e.g., WO95/12389. See also, WO96/11209. See also, U.S. Pat.No. 4,595,700. See also, U.S. Pat. No. 6,013,649.

[0014] A wide variety of hydroxamate compounds also have been reportedto inhibit MMPs. Such compounds reportedly include hydroxamates having acarbon backbone. See, e.g., WIPO Int'l Pub. No. WO 95/29892. See also,WIPO Int'l Pub. No. WO 97/24117. See also, WIPO Int'l Pub. No. WO97/49679. See also, European Patent No. EP 0 780 386. Such compoundsalso reportedly include hydroxamates having peptidyl backbones orpeptidomimetic backbones. See, e.g, WIPO Int'l Pub. No. WO 90/05719. Seealso, WIPO Int'l Pub. No. WO 93/20047. See also, WIPO Int'l Pub. No. WO95/09841. See also, WIPO Int'l Pub. No. WO 96/06074. See also, Schwartzet al., Progr. Med. Chem., 29:271-334(1992). See also, Rasmussen et al.,PharmacoL Ther., 75(1): 69-75 (1997). See also, Denis et al., Invest NewDrugs, 15(3): 175-185 (1997). Sulfamato hydroxamates have additionallybeen reported to inhibit MMPs. See, WIPO Int'l Pub. No. WO 00/46221. Andvarious aromatic sulfone hydroxamates have been reported to inhibitMMPs. See, WIPO Int'l Pub. No. WO 99/25687. See also, WIPO Int'l Pub.No. WO 00/50396. See also, WIPO Int'l Pub. No. WO 00/69821.

[0015] It is often advantageous for an MMP inhibitor drug to target acertain MMP(s) over another MMP(s). For example, it is typicallypreferred to inhibit MMP-2, MMP-3, MMP-9, and/or MMP-13 (particularlyMMP-13) when treating and/or preventing cancer, inhibiting ofmetastasis, and inhibiting angiogenesis. It also is typically preferredto inhibit MMP-13 when preventing and/or treating osteoarthritis. See,e.g., Mitchell et al., J Clin. Invest., 97:761-768 (1996). See also,Reboul et al., J Clin. Invest., 97:2011-2019 (1996). Normally, however,it is preferred to use a drug that has little or no inhibitory effect onMMP-1 and MMP-14. This preference stems from the fact that both MMP-1and MMP-14 are involved in several homeostatic processes, and inhibitionof MMP-1 and/or MMP-14 consequently tends to interfere with suchprocesses.

[0016] Many known MMP inhibitors exhibit the same or similar inhibitoryeffects against each of the MMPs. For example, batimastat (apeptidomimetic hydroxamate) has been reported to exhibit IC₅₀ values offrom about 1 to about 20 nM against each of MMP-1, MMP-2, MMP-3, MMP-7,and MMP-9. Marimastat (another peptidomimetic hydroxamate) has beenreported to be another broad-spectrum MMP inhibitor with an enzymeinhibitory spectrum similar to batimastat, except that Marimastatreportedly exhibited an IC₅₀ value against MMP-3 of 230 nM. SeeRasmussen et al., Pharmacol. Ther., 75(1): 69-75 (1997).

[0017] Meta analysis of data from Phase I/II studies using Marimastat inpatients with advanced, rapidly progressive, treatment-refractory solidtumor cancers (colorectal, pancreatic, ovarian, and prostate) indicateda dose-related reduction in the rise of cancer-specific antigens used assurrogate markers for biological activity. Although Marimastat exhibitedsome measure of efficacy via these markers, toxic side effectsreportedly were observed. The most common drug-related toxicity ofMarimastat in those clinical trials was musculoskeletal pain andstiffness, often commencing in the small joints in the hands, and thenspreading to the arms and shoulder. A short dosing holiday of 1-3 weeksfollowed by dosage reduction reportedly permits treatment to continue.See Rasmussen et al., Pharmacol. Ther., 75(1): 69-75 (1997). It isthought that the lack of specificity of inhibitory effect among the MMPsmay be the cause of that effect.

[0018] Another enzyme implicated in pathological conditions associatedwith excessive degradation of connective tissue is aggrecanase,particularly aggrecanase-1 (also known as ADAMTS-4). Specifically,articular cartilage contains large amounts of the proteoglycan aggrecan.Proteoglycan aggrecan provides mechanical properties that help articularcartilage in withstanding compressive deformation during jointarticulation. The loss of aggrecan fragments and their release intosynovial fluid caused by proteolytic cleavages is a centralpathophysiological event in osteoarthritis and rheumatoid arthritis. Ithas been reported that two major cleavage sites exist in theproteolytically sensitive interglobular domains at the N-terminal regionof the aggrecan core protein. One of those sites has been reported to becleaved by several matrix metalloproteases. The other site, however, hasbeen reported to be cleaved by aggrecanase-1. Thus, inhibiting excessiveaggrecanase activity provides a method for preventing or treatinginflammatory conditions. See generally, Tang, B. L., “ADAMTS: A NovelFamily of Extracellular Matrix Proteases,” Int'l Journal of Biochemistry& Cell Biology, 33, pp. 33-44 (2001). Such diseases reportedly include,for example, osteoarthritis, rheumatoid arthritis, joint injury,reactive arthritis, acute pyrophosphate arthritis, and psoriaticarthritis. See, e.g., European Patent Application Publ. No. EP 1 081 137A1.

[0019] In addition to inflammatory conditions, there also is evidencethat inhibiting aggrecanase may be used for preventing or treatingcancer. For example, excessive levels of aggrecanase-1 reportedly havebeen observed with a ghoma cell line. It also has been postulated thatthe enzymatic nature of aggrecanase and its similarities with the MMPswould support tumor invasion, metastasis, and angiogenesis. See Tang,Int'l Journal of Biochemistry & Cell Biology, 33, pp. 33-44 (2001).

[0020] Various hydroxamate compounds have been reported to inhibitaggrecanase-1. Such compounds include, for example, those described inEuropean Patent Application Publ. No. EP 1 081 137 A1. Such compoundsalso include, for example, those described in WIPO PCT Int'l Publ. No.WO 00/09000. Such compounds further include, for example, thosedescribed in WIPO PCT Int'l Publ. No. WO 00/59874.

[0021] In view of the importance of hydroxamate compounds and saltsthereof in the prevention or treatment of several NMP- and/oraggrecanase-related pathological conditions and the lack of enzymespecificity exhibited by at least some of the hydroxamates that havebeen in clinical trials, there continues to be a need for hydroxamateshaving greater enzyme inhibition specificity (preferably toward MMP-2,MMP-9, MMP-13, and/or aggrecanase, and particularly toward MMP-13 and/oraggrecanase), while exhibiting little or no inhibition of MMP activityessential to normal bodily function (e.g., tissue turnover and repair).The following disclosure describes hydroxamate compounds and saltsthereof that tend to exhibit such desirable activities.

SUMMARY OF THE INVENTION

[0022] This invention is directed to compounds that inhibit MMP(particularly MMP-2, MMP-9, and/or MMP-13) and/or aggrecanase activity,while generally exhibiting relatively little or no inhibition againstMMP activity essential to normal bodily function (particularly MMP-1 andMMP-14 activity). This invention also is directed to a method forinhibiting MMP and/or aggrecanase activity, particularly pathologicalactivity. Such a method is particularly suitable to be used withmammals, such as humans, other primates (e.g., monkeys, chimpanzees.etc.), companion animals (e.g., dogs, cats, horses. etc.), farm animals(e.g., goats, sheep, pigs, cattle, etc.), laboratory animals (e.g.,mice, rats, etc.), and wild and zoo animals (e.g., wolves, bears, deer,etc.).

[0023] Briefly, therefore, the invention is directed in part to acompound or salt thereof. The compound has a structure corresponding toFormula X:

[0024] The variables Z, R, E, and Y are described in more detail below.

[0025] The present invention also is directed to treatment methods thatcomprise administering a compound described above (orpharmaceutically-acceptable salt thereof) in an effective amount to ahost mammal having a condition associated with pathologicalmetalloprotease and/or aggrecanase activity. A contemplated compound orsalt thereof tends to exhibit, for example, inhibitory activity of oneor more matrix metalloprotease (MMP) enzymes (e.g., MMP-2, MMP-9 andMMP-13), while exhibiting substantially less inhibition of MMP-1 and/orMMP-14. By “substantially less” it is meant that a contemplated compoundexhibits an IC₅₀ value ratio against one or more of MMP-2, MMP-9, orMMP-13 as compared to its IC₅₀ value against MMP-1 and/or MMp-14 (e.g.,IC₅₀ MMP-13:IC₅₀ MMP-1) that is less than about 1:10, preferably lessthan about 1:100, and most preferably less than about 1:1000 in the invitro inhibition assay described in the Example section below.

[0026] In one embodiment, the process comprises administering anabove-described compound or pharmaceutically acceptable salt thereof tothe host animal in an amount effective to prevent or treat thecondition. Such a condition may be, for example, tissue destruction, afibrotic disease, pathological matrix weakening, defective injuryrepair, a cardiovascular disease, a pulmonary disease, a kidney disease,and a central nervous system disease. Specific examples of suchconditions include osteoarthritis, rheumatoid arthritis, septicarthritis, tumor invasion, tumor metastasis, tumor angiogenesis, adecubitis ulcer, a gastric ulcer, a corneal ulcer, periodontal disease,liver cirrhosis, fibrotic lung disease, otosclerosis, atherosclerosis,multiple sclerosis, dilated cardiomyopathy, epidermolysis bullosa,aortic aneurysm, weak injury repair, an adhesion, scarring, congestiveheart failure, coronary thrombosis, emphysema, proteinuria, andAlzheimer's disease.

[0027] In another embodiment, the prevention or treatment methodcomprises administering an above-described compound or pharmaceuticallyacceptable salt thereof to the host animal in an amount effective toinhibit matrix metalloprotease-2, matrix metalloprotease-9, and/ormatrix metalloprotease-13 activity.

[0028] In another embodiment, the prevention or treatment methodcomprises administering an above-described compound or pharmaceuticallyacceptable salt, thereof to the host animal in an amount effective toprevent or treat a condition associated with TNF-α convertase activity.Examples of such a condition include inflammation, a pulmonary disease,a cardiovascular disease, an autoimmune disease, graft rejection, afibrotic disease, cancer, an infectious disease, fever, psoriasis,hemorrhage, coagulation, radiation damage, acute-phase responses ofshock and sepsis, anorexia, and cachexia.

[0029] In another embodiment, the prevention or treatment methodcomprises administering an above-described compound or pharmaceuticallyacceptable salt thereof to the host animal in an amount effective toprevent or treat a condition associated with aggrecanase activity. Sucha condition may be, for example, an inflammatory disease or cancer.

[0030] This invention additionally is directed, in part, topharmaceutical compositions comprising the above-described compounds orpharmaceutically acceptable salts thereof, and the use of thosecompositions in the above-described prevention or treatment processes.

[0031] This invention further is directed, in part, to the use of anabove-described compound or pharmaceutically acceptable salt thereof forproduction of a medicament for use in the treatment of a conditionrelated to MMP activity. As noted above, such a condition may be, forexample, tissue destruction, a fibrotic disease, pathological matrixweakening, defective injury repair, a cardiovascular disease, apulmonary disease, a kidney disease, and a central nervous systemdisease.

[0032] Further benefits of Applicants' invention will be apparent to oneskilled in the art reading this patent.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0033] This detailed description of preferred embodiments is intendedonly to acquaint others skilled in the art with Applicants' invention,its principles, and its practical application so that others skilled inthe art may adapt and apply the invention in its numerous forms, as theymay be best suited to the requirements of a particular use. Thisdetailed description and its specific examples, while indicating thepreferred embodiments of this invention, are intended for purposes ofillustration only. This invention, therefore, is not limited to thepreferred embodiments described in this patent, and may be variouslymodified.

A. Compounds of this Invention

[0034] In accordance with this invention, Applicants have found thatcertain aromatic sulfone hydroxamates tend to be effective towardinhibiting MMPs, particularly those associated with excessive (orotherwise pathological) breakdown of connective tissue. Specifically,Applicants have found that these hydroxamates tend to be effective forinhibiting MMP-2 MMP-9, and/or MMP-13, which can be particularlydestructive to tissue if present or generated in abnormally excessivequantities or concentrations. Applicants also have discovered that manyof these hydroxamates tend to be effective toward inhibitingpathological aggrecanase activity. Applicants have further discoveredthat these hydroxamates tend to be selective toward inhibitingaggrecanase and/or MMPs associated with pathological conditionconditions, and tend to avoid excessive inhibition of MMPs (particularlyMMP-1 and MMP-14) essential to normal bodily function (e.g., tissueturnover and repair). Applicants have found, for example, that thesehydroxamates tend to be particularly active toward inhibiting MMP-2,MMP-9, MMP-13, and/or aggrecanase activity in in vitro assays that aregenerally predictive of in vivo activity, while exhibiting minimalinhibition toward MMP-1 and/or MMP-14 in such assays. Examples of suchin vitro assays are discussed in the example section below. Compounds(or salts) that are particularly useful as selective MMP inhibitorsexhibit, for example, an in vitro IC₅₀ value against one or more ofMMP-2, MMP-9, and MMP-13 that is no greater than about 0.1 times theIC₅₀ value against MMP-1 and/or MMP-14, more preferably no greater thanabout 0.01 times the IC₅₀ value against MMP-1 and/or MMP-14, and evenmore preferably 0.001 times the IC₅₀ value against MMP-1 and/or MMP-14.

[0035] Without being bound by theory, the advantages of the selectivityof a contemplated compound can be appreciated by considering the rolesof the various MMP and aggrecanase enzymes. For example, inhibition ofMMP-1 is believed to be undesirable due to the role of MMP-1 as ahousekeeping enzyme (i.e., helping to maintain normal connective tissueturnover and repair). Inhibition of MMP-1 can lead to toxicities or sideeffects such as such as joint or connective tissue deterioration andpain. On the other hand, MMP-13 is believed to be intimately involved inthe destruction of joint components in diseases such as osteoarthritis.Thus, potent and selective inhibition of MMP-13 is typically highlydesirable because such inhibition can have a positive effect on diseaseprogression in a patient (in addition to having an anti-inflammatoryeffect).

[0036] Another advantage of the compounds and salts of this invention istheir tendency to be selective with respect to tumor necrosis factorrelease and/or tumor necrosis factor receptor release. This provides thephysician with another factor to help select the best drug for aparticular patient. Without being bound by theory, it is believed thatthere are multiple factors to this type of selectivity to be considered.The first is that presence of tumor necrosis factor can be desirable forthe control of cancer in the organism, so long as TNF is not present ina toxic excess. Thus, uncontrolled inhibition of release of TNF can becounterproductive and actually can be considered an adverse side effecteven in cancer patients. In addition, selectivity with respect toinhibition of the release of the tumor necrosis factor receptor can alsobe desirable. The presence of that receptor can be desirable formaintaining a controlled tumor necrosis level in the mammal by bindingexcess TNF.

[0037] Briefly, therefore, this invention is directed, in part, to acompound or salt thereof (particularly a pharmaceutically acceptablesalt thereof). The compound has a structure corresponding to Formula X:

[0038] In some preferred embodiments:

[0039] Z is —C(O)—, —N(R⁶)—, —O—, —S—, —S(O)—, —S(O)₂—, or —N(S(O)₂R⁷)—.In some particularly preferred embodiments, Z is —O—. In otherparticularly preferred embodiments, Z is —N(R⁶)—.

[0040] R⁶ is hydrogen, formyl, sulfonic-C₁-C₆-alkyl,C₁-C₆-alkoxycarbonyl-C₁-C₆-alkyl, carboxy-C₁-C₆-alkyl,C₁-C₆-alkylcarbonyl-C₁-C₆-alkyl, R⁸R⁹-aminocarbonyl-C₁-C₆-alkyl,C₁-C₆-alkoxycarbonyl-C₁-C₆-alkylcarbonyl, carboxy-C₁-C₆-alkylcarbonyl,C₁-C₆-alkylcarbonyl-C₁-C₆-alkylcarbonyl, C₁-C₆-alkoxycarbonyl, carboxy,C₁-C₆-alkylcarbonyl, R⁸R⁹-aminocarbonyl, aryl-C₁-C₆-alkyl, arylcarbonyl,bis(C₁-C₆-alkoxy-C₁-C₆-alkyl)-C₁-C₆-alkyl, C₁-C₆-alkyl,halo-C₁-C₆-alkyl, trifluoromethyl-C₁-C₆-alkyl,perfluoro-C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl,C₃-C₆-cycloalkyl, heteroarylcarbonyl, heterocyclylcarbonyl, aryl,heterocyclyl, heteroaryl, C₃-C₈-cycloalkyl-C₁-C₆-alkyl,aryloxy-C₁-C₆-alkyl, heteroaryloxy-C₁-C₆-alkyl,heteroaryl-C₁-C₆-alkoxy-C₁-C₆-alkyl, heteroarylthio-C₁-C₆-alkyl,arylsulfonyl, C₁-C₆-alkylsulfonyl, C₅-C₆-heteroarylsulfonyl,carboxy-C₁-C₆-alkyl, aminocarbonyl, C₁-C₆-alkylimino(R¹⁰)carbonyl,arylimino(R¹⁰)carbonyl, C₅-C₆-heterocyclylimino(R¹⁰)carbonyl,arylthio-C₁-C₆-alkyl, C₁-C₆-alkylthio-C₁-C₆-alkyl,arylthio-C₃-C₆-alkenyl, C₁-C₄-alkylthio-C₃-C₆-alkenyl,C₅-C₆-heteroaryl-C₁-C₆-alkyl, halo-C₁-C₆-alkylcarbonyl,hydroxy-C₁-C₆-alkylcarbonyl, thiol-C₁-C₆-alkylcarbonyl, C₃-C₆-alkenyl,C₃-C₆-alkynyl, aryloxycarbonyl, R⁸R⁹-aminoimino(R¹⁰)methyl,R⁸R⁹-amino-C₁-C₅-alkylcarbonyl, hydroxy-C₁-C₅-alkyl, R⁸R⁹-aminocarbonyl,R⁸R⁹-aminocarbonyl-C₁-C₆-alkylcarbonyl, hydroxyaminocarbonyl,R⁸R⁹-aminosulfonyl, R⁸R⁹-aminosulfonyl-C₁-C₆-alkyl,R⁸R⁹-amino-C₁-C₆-alkylsulfonyl, or R⁸R⁹-amino-C₁-C₆-alkyl.

[0041] In some particularly preferred embodiments, R⁶ is C₁-C₆-alkyl,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₃-C₆-cycloalkyl,C₃-C₈-cycloalkyl-C₁-C₆-alkyl, C₁-C₆-alkylsulfonyl, C₃-C₆-alkenyl, orC₃-C₆-alkynyl.

[0042] R⁷ is aryl-C₁-C₆-alkyl, aryl, heteroaryl, heterocyclyl,C₁-C₆-alkyl, C₃-C₆-alkynyl, C₃-C₆-alkenyl, carboxy-C₁-C₆-alkyl, orhydroxy-C₁-C₆-alkyl.

[0043] R⁸ and R⁹ are independently selected from the group consisting ofhydrogen, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkylcarbonyl, arylcarbonyl, aryl,aryl-C₁-C₆-alkyl, heteroaryl, heteroaryl-C₁-C₆-alkyl, C₂-C₆-alkynyl,C₂-C₆-alkenyl, thiol-C₁-C₆-alkyl, C₁-C₆-alkylthio-C₁-C₆-alkyl,cycloalkyl, cycloalkyl-C₁-C₆-alkyl, heterocyclyl-C₁-C₆-alkyl,C₁-C₆-alkoxy-C₁-C₆-alkyl, aryl-C₁-C₆-alkoxy-C₁-C₆-alkyl,C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl,carboxy-C₁-C₆-alkyl, carboxyaryl-C₁-C₆-alkyl, aminocarbonyl-C₁-C₆-alkyl,aryloxy-C₁-C₆-alkyl, heteroaryloxy-C₁-C₆-alkyl, arylthio-C₁-C₆-alkyl,heteroarylthio-C₁-C₆-alkyl, a sulfoxide of any said thio substituents, asulfone of any said thio substituents, trifluoromethyl-C₁-C₆-alkyl,halo-C₁-C₆-alkyl, alkoxycarbonylamino-C₁-C₆-alkyl, andamino-C₁-C₆-alkyl. Here, the amino-C₁-C₆-alkyl nitrogen optionally issubstituted with up to 2 substituents independently selected from thegroup consisting of C₁-C₆-alkyl, aryl-C₁-C₆-alkyl, cycloalkyl, andC₁-C₆-alkylcarbonyl. Preferably, no greater than one of R⁸ and R⁹ ishydroxy.

[0044] Alternatively, R⁸ and R⁹, together with the atom to which theyare bonded, form a 5- to 8-membered heterocyclic or heteroaryl ringcontaining up to 2 heteroatoms independently selected from the groupconsisting of nitrogen, oxygen, and sulfur.

[0045] R¹⁰ is hydrogen, hydroxy, C₁-C₆-alkyl, aryl, aryl-C₁-C₆-alkyl,heteroaryl, heteroaryl-C₁-C₆-alkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl,thiol-C₁-C₆-alkyl, C₁-C₆-alkylthio-C₁-C₆-alkyl, cycloalkyl,cycloalkyl-C₁-C₆-alkyl, heterocyclyl-C₁-C₆-alkyl,C₁-C₆-alkoxy-C₁-C₆-alkyl, aryl-C₁-C₆-alkoxy-C₁-C₆-alkyl,C₁-C₆-alkoxy-C₁-C₆-alkoxy-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl,carboxy-C₁-C₆-alkyl, carboxyaryl-C₁-C₆-alkyl, aminocarbonyl-C₁-C₆-alkyl,aryloxy-C₁-C₆-alkyl, heteroaryloxy-C₁-C₆-alkyl, arylthio-C₁-C₆-alkyl,heteroarylthio-C₁-C₆-alkyl, a sulfoxide of any said thio substituents, asulfone of any said thio substituents, trifluoromethyl-C₁-C₆-alkyl,halo-C₁-C₆-alkyl, alkoxycarbonylamino-C₁-C₆-alkyl, andamino-C₁-C₆-alkyl. Here, the amino-C₁-C₆-alkyl nitrogen optionally issubstituted with up to 2 substituents independently selected from thegroup consisting of C₁-C₆-alkyl, aryl-C₁-C₆-alkyl, cycloalkyl, andC₁-C₆-alkylcarbonyl.

[0046] E is a bond, —C(O)—, or —S—.

[0047] Y is hydrogen, alkyl, alkoxy, haloalkyl, aryl, arylalkyl,cycloalkyl, heteroaryl, hydroxy, aryloxy, arylalkoxy, heteroaryloxy,heteroarylalkyl, perfluoroalkoxy, perfluoroalkylthio,trifluoromethylalkyl, alkenyl, heterocyclyl, cycloalkyl,trifluoromethyl, alkoxycarbonyl, or aminoalkyl. Here, the aryl,heteroaryl, arylalkyl, or heterocyclyl optionally is substituted with upto 2 substituents independently selected from the group consisting ofalkylcarbonyl, halo, nitro, arylalkyl, aryl, alkoxy, trifluoroalkyl,trifluoroalkoxy, and amino. The amino, in turn, optionally issubstituted with up to 2 substituents independently selected from thegroup consisting of alkyl and arylalkyl. In some particularly preferredembodiments, Y comprises a cyclic structure, i.e., Y is optionallysubstituted aryl, arylalkyl, cycloalkyl, heteroaryl, aryloxy,arylalkoxy, heteroaryloxy, heteroarylalkyl, heterocyclyl, or cycloalkyl.In one such embodiment, Y is optionally substituted phenyl. In anothersuch embodiment, Y is optionally substituted phenylmethyl. In stillanother such embodiment, Y is optionally substituted heteraryl. And instill yet another such embodiment, Y is optionally substitutedheteroarylmethyl.

[0048] R is hydrogen, cyano, perfluoroalkyl, trifluoromethoxy,trifluoromethylthio, haloalkyl, trifluoromethylalkyl,arylalkoxycarbonyl, aryloxycarbonyl, hydroxy, halo, alkyl, alkoxy,nitro, thiol, hydroxycarbonyl, aryloxy, arylthio, arylalkyl, aryl,arylcarbonylamino, heteroaryloxy, heteroarylthio, heteroarylalkyl,cycloalkyl, heterocylyloxy, heterocylylthio, heterocylylamino,cycloalkyloxy, cycloalkylthio, heteroarylalkoxy, heteroarylalkylthio,arylalkoxy, arylalkylthio, arylalkylamino, heterocylyl, heteroaryl,arylazo, hydroxycarbonylalkoxy, alkoxycarbonylalkoxy, alkylcarbonyl,arylcarbonyl, arylalkylcarbonyl, alkylcarbonyloxy, arylalkylcarbonyloxy,hydroxyalkyl, hydroxyalkoxy, alkylthio, alkoxyalkylthio, alkoxycarbonyl,aryloxyalkoxyaryl, arylthioalkylthioaryl, aryloxyalkylthioaryl,arylthioalkoxyaryl, hydroxycarbonylalkoxy, hydroxycarbonylalkylthio,alkoxycarbonylalkoxy, alkoxycarbonylalkylthio, amino, aminocarbonyl, oraminoalkyl.

[0049] The nitrogen of an R amino may be unsubstituted. Alternatively,the amino nitrogen may be substituted with up two substituents that areindependently selected from the group consisting of alkyl, aryl,heteroaryl, arylalkyl, cycloalkyl, arylalkoxycarbonyl, alkoxycarbonyl,arylcarbonyl, arylalkylcarbonyl, heteroarylcarbonyl,heteroarylalkylcarbonyl, and alkylcarbonyl. Alternatively, the aminonitrogen optionally may be substituted with two substituents such thatthe two substituents, together with the amino nitrogen, form a 5- to8-member heterocyclyl or heteroaryl ring that: (i) contains from zero totwo additional heteroatoms that are independently selected from thegroup consisting of nitrogen, oxygen, and sulfur; and (ii) optionally issubstituted with up to two substituents independently selected from thegroup consisting of aryl, alkyl, heteroaryl, arylalkyl, heteroarylalkyl,hydroxy, alkoxy, alkylcarbonyl, cycloalkyl, heterocylylalkyl,alkoxycarbonyl, hydroxyalkyl, trifluoromethyl, benzofusedheterocylylalkyl, hydroxyalkoxyalkyl, arylalkoxycarbonyl,hydroxycarbonyl, aryloxycarbonyl, benzofused heterocylylalkoxy,benzofused cycloalkylcarbonyl, heterocyclylalkylcarbonyl, andcycloalkylcarbonyl.

[0050] The nitrogen of an R aminocarbonyl is may be unsubstituted.Alternatively, the aminocarbonyl nitrogen may be the reacted amine of anamino acid. Alternatively, the aminocarbonyl nitrogen may be substitutedwith up to two substituents independently selected from the groupconsisting of alkyl, hydroxyalkyl, hydroxyheteroarylalkyl, cycloalkyl,arylalkyl, trifluoromethylalkyl, heterocylylalkyl, benzofusedheterocylylalkyl, benzofused cycloalkyl, and N,N-dialkylsubstitutedalkylamino-alkyl. Alternatively, the aminocarbonyl nitrogen may besubstituted with two substituents such that the two substituents,together with the aminocarbonyl nitrogen, form a 5- to 8-memberheterocyclyl or heteroaryl ring that optionally is substituted with upto two substituents independently selected from the group consisting ofalkyl, alkoxycarbonyl, nitro, heterocyclylalkyl, hydroxy,hydroxycarbonyl, aryl, arylalkyl, heteroaralkyl, and amino. Here, theamino nitrogen, in turn, optionally is substituted with: (i) twosubstituents independently selected from the group consisting of alkyl,aryl, and heteroaryl; or (ii) two substituents such that the twosubstituents, together with the amino nitrogen, form a 5- to 8-memberheterocyclyl or heteroaryl ring.

[0051] The nitrogen of an R aminoalkyl may be unsubstituted.Alternatively, the aminoalkyl nitrogen may be substituted with up to twosubstituents independently selected from the group consisting of alkyl,aryl, arylalkyl, cycloalkyl, arylalkoxycarbonyl, alkoxycarbonyl, andalkylcarbonyl. Alternatively, the aminoalkyl nitrogen may be substitutedwith two substituents such that the two substituents, together with theaminoalkyl nitrogen, form a 5- to 8-member heterocyclyl or heteroarylring.

[0052] In one particularly preferred embodiment, R is halogen(preferably chloro or fluoro, and even more preferably chloro). Inanother particularly preferred embodiment, R is hydrogen so that thecompound corresponds in structure to Formula XA:

[0053] In other embodiments directed to compounds corresponding instructure to Formula X:

[0054] Z is —C(O)—, —N(R⁶)—, —O—, —S—, or —S(O)₂—. In one particularlypreferred embodiment, Z is —N(R⁶)—. In another particularly preferredembodiment, Z is —O—.

[0055] R⁶ is hydrogen, arylalkoxycarbonyl, alkylcarbonyl, alkyl,alkoxyalkyl, cycloalkyl, heteroarylcarbonyl, heteroaryl,cycloalkylalkyl, alkylsulfonyl, haloalkylcarbonyl, alkenyl, alkynyl, andR⁸R⁹-aminoalkylcarbonyl.

[0056] In some particularly preferred embodiments, R⁶ is hydrogen,aryl-C₁-C₆-alkoxycarbonyl, C₁-C₆-alkoxycarbonyl, C₁-C₆-alkyl (preferablyisopropyl), C₁-C₆-alkoxy-C₁-C₆-alkyl, C₃-C₆-cycloalkyl, heteroaryl,heteroarylcarbonyl, halo-C₁-C₆-alkylcarbonyl, orR⁸R⁹-amino-C₁-C₆-alkylcarbonyl.

[0057] In other particularly preferred embodiments, R⁶ is C₁-C₆-alkyl(preferably ethyl), C₁-C₆-alkoxy-C₁-C₆-alkyl (preferably methoxyethyl),C₃-C₆-cycloalkyl (preferably cyclopropyl), C₃-C₈-cycloalkyl-C₁-C₆-alkyl(preferably cyclopropylmethyl), C₃-C₆-alkenyl (preferably C₃-alkenyl),C₃-C₆-alkynyl (preferably C₃-alkynyl), or C₁-C₆-alkylsulfonyl(preferably methylsulfonyl).

[0058] R⁸ and R⁹ are independently selected from the group consisting ofhydrogen, alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxyalkyl,heteroarylalkyl, cycloalkylalkyl, heterocyclylcarbonyl, haloalkyl, andaminoalkyl. Here, the aminoalkyl nitrogen optionally is substituted withup to two substituents independently selected from the group consistingof alkyl.

[0059] Alternatively, R⁸ and R⁹, together with the atom to which theyare bonded, form a 5- to 8-membered heterocyclyl or heteroarylcontaining up to 3 (in many instances, no greater than 2) heteroatomsindependently selected from the group consisting of nitrogen, oxygen,and sulfur. Here, any such heterocyclyl or heteroaryl (particularlyheterocyclyl) optionally is substituted with one or more substituentsindependently selected from the group consisting of hydroxy, keto,carboxy, alkoxyalkyl, hydroxyalkyl, hydroxyalkoxyalkyl,alkoxycarbonylalkyl, heterocyclylalkyl, alkoxycarbonyl, and aminoalkyl.The aminoalkyl nitrogen, in turn, optionally is substituted with up totwo substituents independently selected from the group consisting ofalkyl.

[0060] E is a bond, —C(O)—, or —S—.

[0061] Y is cycloalkyl, 2,3-dihydroindolyl, heterocyclyl, aryl,heteroaryl, arylalkyl, or heteroarylalkyl. Here, the cycloalkyl,2,3-dihydroindolyl, heterocyclyl, aryl, heteroaryl, arylalkyl, orheteroarylalkyl optionally is substituted with one or more substituentsindependently selected from the group consisting of halogen, hydroxy,keto, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkoxy, alkylcarbonyl,haloalkoxy, alkylthio, alkoxyalkyl, alkoxycarbonylalkyl, cycloalkyl,cycloalkylalkyl, cycloalkyloxy, cycloalkylalkoxy, cycloalkylalkoxyalkyl,aryl, arylalkyl, arylalkoxy, heterocyclyl, heterocyclylalkyl,heteroaryl, heteroarylcarbonyl, heterocyclylcarbonylalkyl,alkylsulfonyl, amino, aminoalkyl, and aminocarbonyl. These optionalsubstituents, in turn, optionally are substituted with one or moresubstituents independently selected from the group consisting ofhalogen, nitro, alkyl, haloalkyl, alkoxy, haloalkoxy, and alkylcarbonyl.Additionally, the nitrogen of the amino, aminoalkyl, or aminocarbonyloptionally is substituted with up to two substituents independentlyselected from the group consisting of alkyl and cycloalkylalkyl.

[0062] In some preferred embodiments, E is —C(O)—, and Y isheterocyclyl, aryl (particularly phenyl), heteroaryl, or arylmethyl(particularly phenylmethyl). Here, the heterocyclyl, aryl, heteroaryl,or arylmethyl optionally is substituted with one or more substituentsindependently selected from the group consisting of halogen, hydroxy,C₁-C₆-alkyl, halo-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, C₂-C₆-alkenyl,C₁-C₆-alkoxy, C₁-C₆-alkylcarbonyl, halo-C₁-C₆-alkoxy, C₁-C₆-alkylthio,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxycarbonyl-C₁-C₆-alkyl,C₃-C₆-cycloalkyl, aryl, aryl-C₁-C₆-alkyl, aryl-C₁-C₆-alkoxy,heterocyclyl, heterocyclyl-C₁-C₆-alkyl, heteroaryl, heteroarylcarbonyl,heterocyclylcarbonyl-C₁-C₆-alkyl, amino, and amino-C₁-C₆-alkyl. Theseoptional substituents, in turn, are optionally substituted with one ormore substituents independently selected from the group consisting ofhalogen, nitro, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, C₁-C₆-alkoxy, andC₁-C₆-alkylcarbonyl. Additionally, the nitrogen of the amino oramino-C₁-C₆-alkyl optionally is substituted with up to two substituentsindependently selected from the group consisting of C₁-C₆-alkyl andC₃-C₆-cycloalkyl-C₁-C₆-alkyl.

[0063] In other preferred embodiments, E is —C(O)—, and Y is aryl(particularly phenyl), heteroaryl, arylmethyl (particularlyphenylmethyl), or heteroarylmethyl. The aryl, heteroaryl, arylmethyl, orheteroarylmethyl optionally is substituted with one or more substituentsindependently selected from the group consisting of halogen,C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, C₂-C₆-alkenyl, C₁-C₆-alkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₃-C₆-cycloalkyl-C₁-C₆-alkyl,C₃-C₆-cycloalkyloxy, C₃-C₆-cycloalkyl-C₁-C₆-alkoxy,C₃-C₆-cycloalkyl-C₁-C₆-alkoxy-C₁-C₆-alkyl, heterocyclyl-C₁-C₆-alkyl,amino, and amino-C₁-C₆-alkyl. And the nitrogen of the amino oramino-C₁-C₆-alkyl optionally is substituted with up to two substituentsindependently selected from the group consisting of C₁-C₆-alkyl. In somesuch preferred embodiments, Y is optionally substituted phenyl. Suchcompounds include, for example:

[0064] In other such preferred embodiments, Y is optionally substitutedheteroaryl. Such compounds include, for example, compounds wherein Y isoptionally substituted thienyl:

[0065] In other preferred embodiments, E is a bond, and Y is aryl(particularly phenyl), 2,3-dihydroindolyl, heterocyclyl, or heteroaryl.The aryl, 2,3-dihydroindolyl, heterocyclyl, or heteroaryl optionally issubstituted with one or more substituents independently selected fromthe group consisting of halogen, keto, hydroxy, C₁-C₆-alkyl,C₁-C₆-alkoxy, halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy, aryl, aminocarbonyl,and C₁-C₆-alkylsulfonyl. These optional substituents, in turn, also areoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, halo-C₁-C₆-alkyl, andhalo-C₁-C₆-alkoxy. Additionally, the nitrogen of the aminocarbonyloptionally is substituted with up to 2 substituents independentlyselected from the group consisting of C₁-C₆-alkyl.

[0066] In other preferred embodiments, E is a bond, and Y is heteroaryl,aryl (particularly phenyl), or heterocyclyl. The heteroaryl, aryl, orheterocyclyl optionally is substituted with one or more substituentsindependently selected from the group consisting of halogen,C₁-C₆-alkyl, C₁-C₆-alkoxy, and aryl. The optional aryl substituent(s),in turn, optionally is/are substituted with one or more substituentsindependently selected from the group consisting of halo-C₁-C₆-alkyl.

[0067] In other preferred embodiments, E is —S—, and Y is cycloalkyl,aryl, arylmethyl, or heteroaryl. The cycloalkyl, aryl (particularlyphenyl), arylmethyl (particularly phenylmethyl), or heteroaryloptionally is substituted with one or more substituents independentlyselected from the group consisting of halogen, halo-C₁-C₆-alkyl, andhalo-C₁-C₆-alkoxy.

[0068] In other preferred embodiments, E is —S—, and Y is heteraryl.

[0069] In the above embodiments, R preferably is halogen (preferablychloro or fluoro, and even more preferably chloro). Alternatively, Rpreferably is hydrogen so that the compound corresponds in structure toFormula XA (shown above).

B. Preparation of Useful Compounds

[0070] Exemplary chemical transformations that can be useful forpreparing compounds and salts of this invention are described in detailin, for example, WIPO Int'l Publ. Nos. WO 00/69821 (published Nov. 23,2000); WO 00/50396 (published Aug. 31, 2000); and 99/25687 (publishedMay 27, 1999). These references are hereby incorporated by referenceinto this patent. The reader also is referred to the Example sectionbelow, which describes the preparation of numerous compounds and saltsof this invention.

C. Salts of the Compounds of this Invention

[0071] The compounds of this invention can be used in the form of saltsderived from inorganic or organic acids. Depending on the particularcompound, a salt of the compound may be advantageous due to one or moreof the salt's physical properties, such as enhanced pharmaceuticalstability in differing temperatures and humidities, or a desirablesolubility in water or oil. In some instances, a salt of a compound alsomay be used as an aid in the isolation, purification, and/or resolutionof the compound.

[0072] Where a salt is intended to be administered to a patient (asopposed to, for example, being used in an in vitro context), the saltpreferably is pharmaceutically acceptable. Pharmaceutically acceptablesalts include salts commonly used to form alkali metal salts and to formaddition salts of free acids or free bases. In general, these saltstypically may be prepared by conventional means with a compound of thisinvention by reacting, for example, the appropriate acid or base withthe compound.

[0073] Pharmaceutically-acceptable acid addition salts of the compoundsof this invention may be prepared from an inorganic or organic acid.Examples of suitable inorganic acids include hydrochloric, hydrobromicacid, hydroionic, nitric, carbonic, sulfuric, and phosphoric acid.Suitable organic acids generally include, for example, aliphatic,cycloaliphatic, aromatic, araliphatic, heterocyclyl, carboxylic, andsulfonic classes of organic acids. Specific examples of suitable organicacids include acetate, trifluoroacetate, formate, propionate, succinate,glycolate, gluconate, digluconate, lactate, malate, tartaric acid,citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate,glutamate, benzoate, anthranilic acid, mesylate, stearate, salicylate,p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate),methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate,toluenesulfonate, 2-hydroxyethanesulfonate, sufanilate,cyclohexylaminosulfonate, algenic acid, b-hydroxybutyric acid,galactarate, galacturonate, adipate, alginate, bisulfate, butyrate,camphorate, camphorsulfonate, cyclopentanepropionate, dodecylsulfate,glycoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate,nicotinate, 2-naphthalesulfonate, oxalate, palmoate, pectinate,persulfate, 3-phenylpropionate, picrate, pivalate, thiocyanate,tosylate, and undecanoate.

[0074] Pharmaceutically-acceptable base addition salts of the compoundsof this invention include, for example, metallic salts and organicsalts. Preferred metallic salts include alkali metal (group Ia) salts,alkaline earth metal (group IIa) salts, and other physiologicalacceptable metal salts. Such salts may be made from aluminum, calcium,lithium, magnesium, potassium, sodium, and zinc. Preferred organic saltscan be made from tertiary amines and quaternary amine salts, such astromethamine, diethylamine, N,N′-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine(N-methylglucamine), and procaine. Basic nitrogen-containing groups canbe quaternized with agents such as lower alkyl (C₁-C₆) halides (e.g.,methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides),dialkyl sulfates (e.g., dimethyl, diethyl, dibuytl, and diamylsulfates), long chain halides (e.g., decyl, lauryl, myristyl, andstearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyland phenethyl bromides), and others.

[0075] Particularly preferred salts of the compounds of this inventioninclude hydrochloric acid (HCl) salts and trifluoroacetate (CF₃COOH orTFA) salts.

D. Preventing or Treating Conditions Using the Compounds and Salts ofthis Invention

[0076] One embodiment of this invention is directed to a process forpreventing or treating a pathological condition associated with MMPactivity in a mammal (e.g., a human, companion animal, farm animal,laboratory animal, zoo animal, or wild animal) having or disposed tohaving such a condition. Such a condition may be, for example, tissuedestruction, a fibrotic disease, pathological matrix weakening,defective injury repair, a cardiovascular disease, a pulmonary disease,a kidney disease, and a central nervous system disease. Specificexamples of such conditions include osteoarthritis, rheumatoidarthritis, septic arthritis, tumor invasion, tumor metastasis, tumorangiogenesis, a decubitis ulcer, a gastric ulcer, a corneal ulcer,periodontal disease, liver cirrhosis, fibrotic lung disease,otosclerosis, atherosclerosis, multiple sclerosis, dilatedcardiomyopathy, epidermolysis bullosa, aortic aneurysm, weak injuryrepair, an adhesion, scarring, congestive heart failure, coronarythrombosis, emphysema, proteinuria, and Alzheimer's disease.

[0077] The condition may alternatively (or additionally) be associatedwith TNF-α convertase activity. Examples of such a condition includeinflammation (e.g., rheumatoid arthritis), autoimmune disease, graftrejection, multiple sclerosis, a fibrotic disease, cancer, an infectiousdisease (e.g., malaria, mycobacterial infection, meningitis, etc.),fever, psoriasis, a cardiovascular disease (e.g., post-ischemicreperfusion injury and congestive heart failure), a pulmonary disease,hemorrhage, coagulation, hyperoxic alveolar injury, radiation damage,acute phase responses like those seen with infections and sepsis andduring shock (e.g., septic shock, hemodynamic shock, etc.), cachexia,and anorexia.

[0078] The condition may alternatively (or additionally) be associatedwith aggrecanase activity. Examples of such a condition includeinflammation diseases (e.g., osteoarthritis, rheumatoid arthritis, jointinjury, reactive arthritis, acute pyrophosphate arthritis, and psoriaticarthritis) and cancer.

[0079] In this patent, the phrase “preventing a condition” meansreducing the risk of (or delaying) the onset of the condition in amammal that does not have the condition, but is predisposed to havingthe condition. In contrast, the phrase “treating a condition” meansameliorating, suppressing, or eradicating an existing condition. Thepathological condition may be, for example: (a) the result ofpathological MMP and/or aggrecanase activity itself, (b) affected by MMPactivity (e.g., diseases associated with TNF-α), and/or (c) affected byaggrecanase activity.

[0080] A wide variety of methods may be used alone or in combination toadminister the hydroxamates and salt thereof described above. Forexample, the hydroxamates or salts thereof may be administered orally,parenterally, by inhalation spray, rectally, or topically. Oraladministration can be advantageous if, for example, the patient isambulatory, not hospitalized, and physically able and sufficientlyresponsible to take drug at the required intervals. This may be trueeven if the person is being treated with more than one drug for one ormore diseases. On the other hand, IV drug administration can beadvantageous in, for example, a hospital setting where the dose (andthus the blood levels) can be well controlled. A compound or salt ofthis invention also can be formulated for IM administration if desired.This route of administration may be desirable for administering prodrugsor regular drug delivery to patients that are either physically weak orhave a poor compliance record or require constant drug blood levels.

[0081] Typically, a compound (or pharmaceutically acceptable saltthereof) described in this patent is administered in an amount effectiveto inhibit a target MMP(s). The target MMP is/are typically MMP-2,MMP-9, and/or MMP-13, with MMP-13 often being a particularly preferredtarget. The preferred total daily dose of the hydroxamate or saltthereof (administered in single or divided doses) is typically fromabout 0.001 to about 100 mg/kg, more preferably from about 0.001 toabout 30 mg/kg, and even more preferably from about 0.01 to about 10mg/kg (i.e., mg hydroxamate or salt thereof per kg body weight). Dosageunit compositions can contain such amounts or submultiples thereof tomake up the daily dose. In many instances, the administration of thecompound or salt will be repeated a plurality of times. Multiple dosesper day typically may be used to increase the total daily dose, ifdesired.

[0082] Factors affecting the preferred dosage regimen include the type,age, weight, sex, diet, and condition of the patient; the severity ofthe pathological condition; the route of administration; pharmacologicalconsiderations, such as the activity, efficacy, pharmacokinetic, andtoxicology profiles of the particular hydroxamate or salt thereofemployed; whether a drug delivery system is utilized; and whether thehydroxamate or salt thereof is administered as part of a drugcombination. Thus, the dosage regimen actually employed can vary widely,and, therefore, can deviate from the preferred dosage regimen set forthabove.

E. Pharmaceutical Compositions Containing the Compounds and Salts ofthis Invention

[0083] This invention also is directed to pharmaceutical compositionscomprising a hydroxamate or salt thereof described above, and to methodsfor making pharmacetucal compositions (or medicaments) comprising ahydroxamate or salt thereof described above.

[0084] The preferred composition depends on the method ofadministration, and typically comprises one or more conventionalpharmaceutically acceptable carriers, adjuvants, and/or vehicles.Formulation of drugs is generally discussed in, for example, Hoover,John E., Remington's Pharmaceutical Sciences (Mack Publishing Co.,Easton, Pa.: 1975). See also, Liberman, H. A. See also, Lachman, L.,eds., Pharmaceutical Dosage Forms (Marcel Decker, New York, N.Y., 1980).

[0085] Solid dosage forms for oral administration include, for example,capsules, tablets, pills, powders, and granules. In such solid dosageforms, the hydroxamates or salts thereof are ordinarily combined withone or more adjuvants. If administered per os, the hydroxamates or saltsthereof can be mixed with lactose, sucrose, starch powder, celluloseesters of alkanoic acids, cellulose alkyl esters, talc, stearic acid,magnesium stearate, magnesium oxide, sodium and calcium salts ofphosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate,polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted orencapsulated for convenient administration. Such capsules or tablets cancontain a controlled-release formulation, as can be provided in adispersion of the hydroxamate or salt thereof in hydroxypropylmethylcellulose. In the case of capsules, tablets, and pills, the dosage formsalso can comprise buffering agents, such as sodium citrate, or magnesiumor calcium carbonate or bicarbonate. Tablets and pills additionally canbe prepared with enteric coatings.

[0086] Liquid dosage forms for oral administration include, for example,pharmaceutically acceptable emulsions, solutions, suspensions, syrups,and elixirs containing inert diluents commonly used in the art (e.g.,water). Such compositions also can comprise adjuvants, such as wetting,emulsifying, suspending, flavoring (e.g., sweetening), and/or perfumingagents.

[0087] “Parenteral administration” includes subcutaneous injections,intravenous injections, intramuscular injections, intrasternalinjections, and infusion. Injectable preparations (e.g., sterileinjectable aqueous or oleaginous suspensions) can be formulatedaccording to the known art using suitable dispersing, wetting agents,and/or suspending agents. Acceptable vehicles and solvents include, forexample, water, 1,3-butanediol, Ringer's solution, isotonic sodiumchloride solution, bland fixed oils (e.g., synthetic mono- ordiglycerides), fatty acids (e.g., oleic acid), dimethyl acetamide,surfactants (e.g., ionic and non-ionic detergents), and/or polyethyleneglycols.

[0088] Formulations for parenteral administration may, for example, beprepared from sterile powders or granules having one or more of thecarriers or diluents mentioned for use in the formulations for oraladministration. The hydroxamates or salts thereof can be dissolved inwater, polyethylene glycol, propylene glycol, ethanol, corn oil,cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride,and/or various buffers.

[0089] Suppositories for rectal administration can be prepared by, forexample, mixing the drug with a suitable nonirritating excipient that issolid at ordinary temperatures, but liquid at the rectal temperature andwill therefore melt in the rectum to release the drug. Suitableexcipients include, for example, such as cocoa butter; synthetic mono-,di-, or triglycerides; fatty acids; and/or polyethylene glycols

[0090] “Topical administration” includes the use of transdermaladministration, such as transdermal patches or iontophoresis devices.

[0091] Other adjuvants and modes of administration known in thepharmaceutical art may also be used.

F. Definitions

[0092] The term “alkyl” (alone or in combination with another term(s))means a straight-or branched-chain saturated hydrocarbyl group typicallycontaining from 1 to about 20 carbon atoms, more typically from about 1to about 8 carbon atoms, and even more typically from about 1 to about 6carbon atoms. Examples of such groups include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl,hexyl, octyl, and the like.

[0093] The term “alkenyl” (alone or in combination with another term(s))means a straight- or branched-chain hydrocarbyl group containing one ormore double bonds and typically from 2 to about 20 carbon atoms, moretypically from about 2 to about 8 carbon atoms, and even more typicallyfrom about 2 to about 6 carbon atoms. Examples of such groups includeethenyl (vinyl); 2-propenyl; 3-propenyl; 1,4-pentadienyl;1,4-butadienyl; 1-butenyl; 2-butenyl; 3-butenyl; decenyl; and the like.

[0094] The term “alkynyl” (alone or in combination with another term(s))means a straight- or branched-chain hydrocarbyl group containing one ormore triple bonds and typically from 2 to about 20 carbon atoms, moretypically from about 2 to about 8 carbon atoms, and even more typicallyfrom about 2 to about 6 carbon atoms. Examples of such groups includeethynyl, 2-propynyl, 3-propynyl, decynyl, 1-butynyl, 2-butynyl,3-butynyl, and the like.

[0095] The term “carbocyclyl” (alone or in combination with anotherterm(s)) means a saturated cyclic, partially saturated cyclic, or arylhydrocarbyl group containing from 3 to 14 carbon ring atoms (“ringatoms” are the atoms bound together to form the ring or rings of acyclic group). A carbocyclyl may be a single ring, which typicallycontains from 3 to 6 ring atoms. Examples of such single-ringcarbocyclyls include cyclopropanyl, cyclobutanyl, cyclopentyl,cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl,cyclohexadienyl, and phenyl. A carbocyclyl alternatively may be 2 or 3rings fused together, such as naphthalenyl, tetrahydronaphthalenyl (alsoknown as “tetralinyl”), indenyl, isoindenyl, indanyl, bicyclodecanyl,anthracenyl, phenanthrene, benzonaphthenyl (also known as “phenalenyl”),fluoreneyl, decalinyl, and norpinanyl.

[0096] The term “cycloalkyl” (alone or in combination with anotherterm(s)) means a saturated cyclic hydrocarbyl group containing from 3 to14 carbon ring atoms. A cycloalkyl may be a single carbon ring, whichtypically contains from 3 to 6 carbon ring atoms. Examples ofsingle-ring cycloalkyls include cyclopropanyl, cyclobutanyl,cyclopentyl, and cyclohexyl. A cycloalkyl alternatively may be 2 or 3carbon rings fused together, such as, decalinyl or norpinanyl.

[0097] The term “aryl” (alone or in combination with another term(s))means an aromatic carbocyclyl containing from 6 to 14 carbon ring atoms.Examples of aryls include phenyl, naphthalenyl, and indenyl.

[0098] In some instances, the number of carbon atoms in a hydrocarbylgroup (e.g., alkyl, alkenyl, alkynyl, or cycloalkyl) is indicated by theprefix “C_(x)-C_(y)-”, wherein x is the minimum and y is the maximumnumber of carbon atoms in the group. Thus, for example, “C₁-C₆-alkyl”refers to an alkyl group containing from 1 to 6 carbon atoms.Illustrating further, C₃-C₆-cycloalkyl means a saturated hydrocarbylring containing from 3 to 6 carbon ring atoms.

[0099] The term “hydrogen” (alone or in combination with anotherterm(s)) means a hydrogen radical, and may be depicted as —H.

[0100] The term “hydroxy” (alone or in combination with another term(s))means —OH.

[0101] The term “nitro” (alone or in combination with another term(s))means —NO₂.

[0102] The term “cyano” (alone or in combination with another term(s))means —CN, which also may be depicted as or —COOH:

[0103] The term “keto” (alone or in combination with another term(s))means an oxo radical, and may be depicted as ═O.

[0104] The term “carboxy” (alone or in combination with another term(s))means —C(O)—OH, which also may be depicted as:

[0105] The term “amino” (alone or in combination with another term(s))means —NH₂. The term “monosubstituted amino” (alone or in combinationwith another term(s)) means an amino group wherein one of the hydrogenradicals is replaced by a non-hydrogen substituent. The term“disubstituted amino” (alone or in combination with another term(s))means an amino group wherein both of the hydrogen atoms are replaced bynon-hydrogen substituents, which may be identical or different.

[0106] The term “halogen” (alone or in combination with another term(s))means a fluorine radical (which may be depicted as —F), chlorine radical(which may be depicted as —Cl), bromine radical (which may be depictedas —Br), or iodine radical (which may be depicted as —I). Typically, afluorine radical or chlorine radical is preferred.

[0107] If a group is described as being “substituted”, at least onehydrogen on the group is replaced with a non-hydrogen substituent. Thus,for example, a substituted alkyl group is an alkyl group wherein atleast one hydrogen on the alkyl group is replaced with a non-hydrogensubstituent. It should be recognized that if there are more than onesubstitutions on a group, each non-hydrogen substituent may be identicalor different.

[0108] If a group is described as being “optionally substituted”, thegroup may be either substituted or not substituted.

[0109] The prefix “halo” indicates that the group to which the prefix isattached is substituted with one or more independently selected halogenradicals. For example, haloalkyl means an alkyl group wherein at leastone hydrogen radical is replaced with a halogen radical. Examples ofhaloalkyls include chloromethyl, 1-bromoethyl, fluoromethyl,difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and the like.Illustrating further, “haloalkoxy” means an alkoxy group wherein atleast one hydrogen radical is replaced by a halogen radical. Examples ofhaloalkoxy groups include chlormethoxy, 1-bromoethoxy, fluoromethoxy,difluoromethoxy, trifluoromethoxy (also known as “perfluoromethyoxy”),1,1,1,-trifluoroethoxy, and the like. It should be recognized that if agroup is substituted by more than one halogen radical, those halogenradicals may be identical or different.

[0110] The prefix “perhalo” indicates that every hydrogen radical on thegroup to which the prefix is attached is replaced with independentlyselected halogen radicals, i.e., each hydrogen radical on the group isreplaced with a halogen radical. If all the halogen radicals areidentical, the prefix typically will identify the halogen radical. Thus,for example, the term “perfluoro” means that every hydrogen radical onthe group to which the prefix is attached is substituted with a fluorineradical. To illustrate, the term “prefluoroalkyl” means an alkyl groupwherein each hydrogen radical is replaced with a fluorine radical.Examples of perfluoroalkyl groups include trifluoromethyl (—CF₃),perfluorobutyl, perfluoroisopropyl, perfluorododecyl, perfluorodecyl,and the like. To illustrate further, the term “perfluoroalkoxy” means analkoxy group wherein each hydrogen radical is replaced with a fluorineradical. Examples of perfluoroalkoxy groups include trifluoromethoxy(—O—CF₃), perfluorobutoxy, perfluoroisopropoxy, perfluorododecoxy,perfluorodecoxy, and the like.

[0111] The term “carbonyl” (alone or in combination with anotherterm(s)) means —C(O)—, which also may be depicted as:

[0112] This term also is intended to encompass a hydrated carbonylgroup, i.e., —C(OH)₂—.

[0113] The term “aminocarbonyl” (alone or in combination with anotherterm(s)) means —C(O)—NH₂, which also may be depicted as:

[0114] The term “oxy” (alone or in combination with another term(s))means an ether group, and may be depicted as —O—.

[0115] The term “alkoxy” (alone or in combination with another term(s))means an alkylether group, i.e., —O-alkyl. Examples of such a groupinclude methoxy (—O—CH₃), ethoxy, n-propoxy, isopropoxy, n-butoxy,iso-butoxy, sec-butoxy, tert-butoxy, and the like.

[0116] The term “alkylcarbonyl” (alone or in combination with anotherterm(s)) means —C(O)-alkyl. For example, “ethylcarbonyl” may be depictedas:

[0117] The term “aminoalkylcarbonyl” (alone or in combination withanother term(s)) means —C(O)-alkyl-NH₂. For example,“aminomethylcarbonyl” may be depicted as:

[0118] The term “alkoxycarbonyl” (alone or in combination with anotherterm(s)) means —C(O)—O-alkyl. For example, “ethoxycarbonyl” may bedepicted as:

[0119] The term “carbocyclylcarbonyl” (alone or in combination withanother term(s)) means —C(O)-carbocyclyl. For example, “phenylcarbonyl”may be depicted as:

[0120] Similarly, the term “heterocyclylcarbonyl” (alone or incombination with another term(s)) means —C(O)-heterocyclyl.

[0121] The term “carbocyclylalkylcarbonyl” (alone or in combination withanother term(s)) means —C(O)-alkyl-carbocyclyl. For example,“phenylethylcarbonyl” may be depicted as:

[0122] Similarly, the term “heterocyclylalkylcarbonyl” (alone or incombination with another term(s)) means —C(O)-alkyl-heterocyclyl.

[0123] The term “carbocyclyloxycarbonyl” (alone or in combination withanother term(s)) means —C(O)—O-carbocyclyl. For example,“phenyloxycarbonyl” may be depicted as:

[0124] The term “carbocyclylalkoxycarbonyl” (alone or in combinationwith another term(s)) means —C(O)—O-alkyl-carbocyclyl. For example,“phenylethoxycarbonyl” may be depicted as:

[0125] The term “thio” or “thia” (alone or in combination with anotherterm(s)) means a thiaether group, i.e., an ether group wherein the etheroxygen atom is replaced by a sulfur atom. Such a group may be depictedas —S—. This, for example, “alkyl-thio-alkyl” means alkyl-S-alkyl.

[0126] The term “thiol” or “sulfhydryl” (alone or in combination withanother term(s)) means a sulfhydryl group, and may be depicted as —SH.

[0127] The term “(thiocarbonyl)” (alone or in combination with anotherterm(s)) means a carbonyl wherein the oxygen atom has been replaced witha sulfur. Such a group may be depicted as —C(S)—, and also may bedepicted as:

[0128] The term “alkyl(thiocarbonyl)” (alone or in combination withanother term(s)) means —C(S)-alkyl. For example, “ethyl(thiocarbonyl)”may be depicted as:

[0129] The term “alkoxy(thiocarbonyl)” (alone or in combination withanother term(s)) means —C(S)—O-alkyl. For example,“ethoxy(thiocarbonyl)” may be depicted as:

[0130] The term “carbocyclyl(thiocarbonyl)” (alone or in combinationwith another term(s)) means —C(S)-carbocyclyl. For example,“phenyl(thiocarbonyl)” may be depicted as:

[0131] Similarly, the term “heterocyclyl(thiocarbonyl)” (alone or incombination with another term(s)) means —C(S)-heterocyclyl.

[0132] The term “carbocyclylalkyl(thiocarbonyl)” (alone or incombination with another term(s)) means —C(S)-alkyl-carbocyclyl. Forexample, “phenylethyl(thiocarbonyl)” may be depicted as:

[0133] Similarly, the term “heterocyclylalkyl(thiocarbonyl)” (alone orin combination with another term(s)) means —C(S)-alkyl-heterocyclyl.

[0134] The term “carbocyclyloxy(thiocarbonyl)” (alone or in combinationwith another term(s)) means —C(S)—O-carbocyclyl. For example,“phenyloxy(thiocarbonyl)” may be depicted as:

[0135] The term “carbocyclylalkoxy(thiocarbonyl)” (alone or incombination with another term(s)) means —C(S)—O-alkyl-carbocyclyl. Forexample, “phenylethoxy(thiocarbonyl)” may be depicted as:

[0136] The term “sulfonyl” (alone or in combination with anotherterm(s)) means —S(O)₂—, which also may be depicted as:

[0137] Thus, for example, “alkyl-sulfonyl-alkyl” meansalkyl-S(O)₂-alkyl.

[0138] The term “aminosulfonyl” (alone or in combination with anotherterm(s)) means —S(O)₂—NH₂, which also may be depicted as:

[0139] The term “sulfoxido” (alone or in combination with anotherterm(s)) means —S(O)—, which also may be depicted as:

[0140] Thus, for example, “alkyl-sulfoxido-alkyl” meansalkyl-S(O)-alkyl.

[0141] The term “heterocyclyl” (alone or in combination with anotherterm(s)) means a saturated or partially saturated ring structurecontaining a total of 3 to 14 ring atoms. At least one of the ring atomsis a heteroatom (i.e., oxygen, nitrogen, or sulfur), with the remainingring atoms being independently selected from the group consisting ofcarbon, oxygen, nitrogen, and sulfur. A heterocyclyl may be a singlering, which typically contains from 3 to 7 ring atoms, more typicallyfrom 3 to 6 ring atoms, and even more typically 5 to 6 ring atoms. Aheterocyclyl alternatively may be 2 or 3 rings fused together.

[0142] The term “heteroaryl” (alone or in combination with anotherterm(s)) means an aromatic ring containing from 5 to 14 ring atoms. Atleast one of the ring atoms is a heteroatom, with the remaining ringatoms being independently selected from the group consisting of carbon,oxygen, nitrogen, and sulfur. A heteroaryl may be a single ring, whichtypically contains from 5 to 7 ring atoms, and more typically from 5 to6 ring atoms. A heteroaryl alternatively may be 2 or 3 rings fusedtogether.

[0143] Examples of single-ring heterocyclyls and heteroaryls includefuranyl, dihydrofurnayl, tetradydrofurnayl, thiophenyl (also known as“thiofuranyl”), dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl,isopyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl,imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl,triazolyl, tetrazolyl, dithiolyl, oxathiolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl,isothiazolidinyl, thiodiazolyl, oxathiazolyl, oxadiazolyl (including1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl (also known as “azoximyl”),1,2,5-oxadiazolyl (also known as “furazanyl”), or 1,3,4-oxadiazolyl),oxatriazolyl (including 1,2,3,4-oxatriazolyl or 1,2,3,5-oxatriazolyl),dioxazolyl (including 1,2,3-dioxazolyl, 1,2,4-dioxazolyl,1,3,2-dioxazolyl, or 1,3,4-dioxazolyl), oxathiazolyl, oxathiolyl,oxathiolanyl, pyranyl (including 1,2-pyranyl or 1,4-pyranyl),dihydropyranyl, pyridinyl (also known as “azinyl”), piperidinyl,diazinyl (including pyridazinyl (also known as “1,2-diazinyl”),pyrimidinyl (also known as “1,3-diazinyl”), or pyrazinyl (also known as“1,4-diazinyl”)), piperazinyl, triazinyl (including s-triazinyl (alsoknown as “1,3,5-triazinyl”), as-triazinyl (also known 1,2,4-triazinyl),and v-triazinyl (also known as “1,2,3-triazinyl”)), oxazinyl (including1,2,3-oxazinyl, 1,3,2-oxazinyl, 1,3,6-oxazinyl (also known as“pentoxazolyl”), 1,2,6-oxazinyl, or 1,4-oxazinyl), isoxazinyl (includingo-isoxazinyl or p-isoxazinyl), oxazolidinyl, isoxazolidinyl,oxathiazinyl (including 1,2,5-oxathiazinyl or 1,2,6-oxathiazinyl),oxadiazinyl (including 1,4,2-oxadiazinyl or 1,3,5,2-oxadiazinyl),morpholinyl, azepinyl, oxepinyl, thiepinyl, and diazepinyl.

[0144] Examples of heterocyclyl and heteroaryl rings having 2 or 3 ringsfused together include, for example, indolizinyl, pyrindinyl,pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl,pyridopyridinyl (including pyrido[3,4-b]-pyridinyl,pyrido[3,2-b]-pyridinyl, or pyrido[4,3-b]-pyridinyl), and pteridinyl.Other examples of fused-ring heterocyclyls include benzo-fusedheterocyclyls, such as indolyl, isoindolyl (also known as“isobenzazolyl” or “pseudoisoindolyl”), indoleninyl (also known as“pseudoindolyl”), isoindazolyl (also known as “benzpyrazolyl”),benzazinyl (including quinolinyl (also known as “1-benzazinyl”) orisoquinolinyl (also known as “2-benzazinyl”)), phthalazinyl,quinoxalinyl, quinazolinyl, benzodiazinyl (including cinnolinyl (alsoknown as “1,2-benzodiazinyl”) or quinazolinyl (also known as“1,3-benzodiazinyl”)), benzopyranyl (including “chromanyl” or“isochromanyl”), benzothiopyranyl (also known as “thiochromanyl”),benzoxazolyl, indoxazinyl (also known as “benzisoxazolyl”), anthranilyl,benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl (also knownas “coumaronyl”), isobenzofuranyl, benzothienyl (also known as“benzothiophenyl”, “thionaphthenyl”, or “benzothiofuiranyl”),isobenzothienyl (also known as “isobenzothiophenyl”,“isothionaphthenyl”, or “isobenzothiofuiranyl”), benzothiazolyl,benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl(including 1,3,2-benzoxazinyl, 1,4,2-benzoxazinyl, 2,3,1-benzoxazinyl,or 3,1,4-benzoxazinyl), benzisoxazinyl (including 1,2-benzisoxazinyl or1,4-benzisoxazinyl), tetrahydroisoquinolinyl, carbazolyl, xanthenyl, andacridinyl.

[0145] As may be seen in the preceding paragraphs, the term “heteroaryl”includes 6-membered ring substituents such as pyridyl, pyrazyl,pyrimidinyl, and pyridazinyl; 5-membered ring substituents such as1,3,5-, 1,2,4- or 1,2,3-tiiazinyl, imidazyl, furanyl, thiophenyl,pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-, or1,3,4-oxadiazolyl and isothiazolyl; 6/5-membered fused ring substituentssuch as benzothiofuranyl, isobenzothiofuranyl, benzisoxazolyl,benzoxazolyl, purinyl, and anthranilyl; and 6/6-membered fused ringssuch as 1,2-, 1,4-, 2,3- and 2,1-benzopyronyl, quinolinyl,isoquinolinyl, cinnolinyl, quinazolinyl, and 1,4-benzoxazinyl.

[0146] A carbocyclyl, heterocyclyl, or heteroaryl optionally can besubstituted with, for example, one or more substituents independentlyselected from the group consisting of halogen, hydroxy, carboxy, keto,alkyl, alkoxy, alkoxyalkyl, alkylcarbonyl (also known as “alkanoyl”),aryl, arylalkyl, arylalkoxy, arylalkoxyalkyl, arylalkoxycarbonyl,cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylalkoxyalkyl,and cycloalkylalkoxycarbonyl. More typically, a carbocyclyl orheterocyclyl may optionally be substituted with, for example, one ormore substituents independently selected from the group consisting ofhalogen, —OH, —C(O)—OH, keto, C₁-C₆-alkyl, C₁-C₆-alkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkylcarbonyl, aryl, aryl-C₁-C₆-alkyl,aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkoxy-C₁-C₆-alkyl,aryl-C₁-C₆-alkoxycarbonyl, cycloalkyl, cycloalkyl-C₁-C₆-alkyl,cycloalkyl-C₁-C₆-alkoxy, cycloalkyl-C₁-C₆-alkoxy-C₁-C₆-alkyl, andcycloalkyl-C₁-C₆-alkoxycarbonyl. The alkyl, alkoxy, alkoxyalkyl,alkylcarbonyl, aryl, arylalkyl, arylalkoxy, arylalkoxyalkyl, orarylalkoxycarbonyl substituent(s) may further be substituted with, forexample, one or more halogen. The aryls or cycloalkyls are typicallysingle-ring groups containing from 3 to 6 ring atoms, and more typicallyfrom 5 to 6 ring atoms.

[0147] An aryl or heteroaryl optionally can be substituted with, forexample, one or more substituents independently selected from the groupconsisting of halogen, —OH, —CN, —NO₂, —SH, —C(O)—OH, amino,aminocarbonyl, aminoalkyl, alkyl, alkylthio, carboxyalkylthio,alkylcarbonyl, alkylcarbonyloxy, alkoxy, alkoxyalkyl, alkoxycarbonyl,alkoxycarbonylalkoxy, alkoxyalkylthio, alkoxycarbonylalkylthio,carboxyalkoxy, alkoxycarbonylalkoxy, carbocyclyl, carbocyclylalkyl,carbocyclyloxy, carbocyclylthio, carbocyclylalkylthio, carbocyclylamino,carbocyclylalkylamino, carbocyclylcarbonylamino, carbocyclylcarbonyl,carbocyclylalkyl, carbonyl, carbocyclylcarbonyloxy,carbocyclyloxycarbonyl, carbocyclylalkoxycarbonyl,carbocyclyloxyalkoxycarbocyclyl, carbocyclylthioalkylthiocarbocyclyl,carbocyclylthioalkoxycarbocyclyl, carbocyclyloxyalkylthiocarbocyclyl,heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylthio,heterocyclylalkylthio, heterocyclylamino, heterocyclylalkylamino,heterocyclylcarbonylamino, heterocyclylcarbonyl,heterocyclylalkylcarbonyl, heterocyclyloxycarbonyl,heterocyclylcarbonyloxy, heterocyclylalkoxycarbonyl,heterocyclyloxyalkoxyheterocyclyl,heterocyclylthioalkylthioheterocyclyl,heterocyclylthioalkoxyheterocyclyl, andheterocyclyloxyalkylthioheterocyclyl. More typically, an aryl orheteroaryl may, for example, optionally be substituted with one or moresubstituents independently selected from the group consisting ofhalogen, —OH, —CN, —NO₂, —SH, —C(O)—OH, amino, aminocarbonyl,amino-C₁-C₆-alkyl, C₁-C₆-alkyl, C₁-C₆-alkylthio,carboxy-C₁-C₆-alkylthio, C₁-C₆-alkylcarbonyl, C₁-C₆-alkylcarbonyloxy,C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxycarbonyl,C₁-C₆-alkoxycarbonyl-C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₆-alkylthio,C₁-C₆-alkoxycarbonyl-C₁-C₆-alkylthio, carboxy-C₁-C₆-alkoxy,C₁-C₆-alkoxycarbonyl-C₁-C₆-alkoxy, aryl, aryl-C₁-C₆-alkyl, aryloxy,arylthio, aryl-C₁-C₆-alkylthio, arylamino, aryl-C₁-C₆-alkylamino,arylcarbonylamino, arylcarbonyl, aryl-C₁-C₆-alkylcarbonyl,arylcarbonyloxy, aryloxycarbonyl, aryl-C₁-C₆-alkoxycarbonyl,aryloxy-C₁-C₆-alkoxyaryl, arylthio-C₁-C₆-alkylthioaryl,arylthio-C₁-C₆-alkoxyaryl, aryloxy-C₁-C₆-alkylthioaryl, cycloalkyl,cycloalkyl-C₁-C₆-alkyl, cycloalkyloxy, cycloalkylthio,cycloalkyl-C₁-C₆-alkylthio, cycloalkylamino,cycloalkyl-C₁-C₆-alkylamino, cycloalkylcarbonylamino,cycloalkylcarbonyl, cycloalkyl-C₁-C₆-alkylcarbonyl,cycloalkylcarbonyloxy, cycloalkyloxycarbonyl,cycloalkyl-C₁-C₆-alkoxycarbonyl, heteroaryl, heteroaryl-C₁-C₆-alkyl,heteroaryloxy, heteroarylthio, heteroaryl-C₁-C₆-alkylthio,heteroarylamino, heteroaryl-C₁-C₆-alkylamino, heteroarylcarbonylamino,heteroarylcarbonyl, heteroaryl-C₁-C₆-alkylcarbonyl,heteroaryloxycarbonyl, heteroarylcarbonyloxy, andheteroaryl-C₁-C₆-alkoxycarbonyl. Here, one or more hydrogens bound to acarbon in any such group may, for example, optionally be replaced withhalogen. In addition, the cycloalkyl, aryl, and heteroaryl are typicallysingle-ring groups containing 3 to 6 ring atoms, and more typically 5 or6 ring atoms.

[0148] In some embodiments, an aryl or heteroaryl optionally issubstituted with one or more substituents independently selected fromthe group consisting of cyano, perfluoroalkyl, trifluoromethoxy,trifluoromethylthio, haloalkyl, trifluoromethylalkyl, aralkoxycarbonyl,aryloxycarbonyl, hydroxy, halo, alkyl, alkoxy, nitro, thiol,hydroxycarbonyl, aryloxy, arylthio, aralkyl, aryl, arylcarbonylamino,heteroaryloxy, heteroarylthio, heteroaralkyl, cycloalkyl,heterocylyloxy, heterocylylthio, heterocylylamino, cycloalkyloxy,cycloalkylthio, heteroaralkoxy, heteroaralkylthio, aralkoxy,aralkylthio, aralkylamino, heterocylyl, heteroaryl, arylazo,hydroxycarbonylalkoxy, alkoxycarbonylalkoxy, alkanoyl, arylcarbonyl,aralkanoyl, alkanoyloxy, aralkanoyloxy, hydroxyalkyl, hydroxyalkoxy,alkylthio, alkoxyalkylthio, alkoxycarbonyl, aryloxyalkoxyaryl,arylthioalkylthioaryl, aryloxyalkylthioaryl, arylthioalkoxyaryl,hydroxycarbonylalkoxy, hydroxycarbonylalkylthio, alkoxycarbonylalkoxy,alkoxycarbonylalkylthio, amino, aminocarbonyl, and aminoalkyl. Here, theamino nitrogen optionally is substituted with:

[0149] (i) up two substituents that are independently selected from thegroup consisting of alkyl, aryl, heteroaryl, aralkyl, cycloalkyl,aralkoxycarbonyl, alkoxycarbonyl, arylcarbonyl, aralkanoyl,heteroarylcarbonyl, heteroaralkanoyl, and alkanoyl; or

[0150] (ii) two substituents such that the two substituents, togetherwith the amino nitrogen, form a 5- to 8-member heterocyclyl orheteroaryl ring that:

[0151] (a) contains from zero to two additional heteroatoms that areindependently selected from the group consisting of nitrogen, oxygen,and sulfur;

[0152] (b) optionally is substituted with up to two substituentsindependently selected from the group consisting of aryl, alkyl,heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, alkanoyl,cycloalkyl, heterocylylalkyl, alkoxycarbonyl, hydroxyalkyl,trifluoromethyl, benzofused heterocylylalkyl, hydroxyalkoxyalkyl,aralkoxycarbonyl, hydroxycarbonyl, aryloxycarbonyl, benzofusedheterocylylalkoxy, benzofused cycloalkylcarbonyl,heterocyclylalkylcarbonyl, and cycloalkylcarbonyl.

[0153] The aminocarbonyl nitrogen is:

[0154] (i) unsubstituted;

[0155] (ii) the reacted amine of an amino acid;

[0156] (iii) substituted with one or two substituents independentlyselected from the group consisting of alkyl, hydroxyalkyl,hydroxyheteroaralkyl, cycloalkyl, aralkyl, trifluoromethylalkyl,heterocylylalkyl, benzofused heterocylylalkyl, benzofused cycloalkyl,and N,N-dialkylsubstituted alkylaminoalkyl; or

[0157] (iv) substituted with two substituents such that the twosubstituents, together with the aminocarbonyl nitrogen, form a 5- to8-member heterocyclyl or heteroaryl ring that optionally is substitutedwith up to two substituents independently selected from the groupconsisting of alkyl, alkoxycarbonyl, nitro, heterocylylalkyl, hydroxy,hydroxycarbonyl, aryl, aralkyl, heteroaralkyl, and amino, wherein theamino nitrogen optionally is substituted with:

[0158] (a) two substituents independently selected from the groupconsisting of alkyl, aryl, and heteroaryl; or

[0159] (b) two substituents such that the two substituents, togetherwith the amino nitrogen, form a 5- to 8-member heterocyclyl orheteroaryl ring.

[0160] The aminoalkyl nitrogen optionally is substituted with:

[0161] (i) up to two substituents independently selected from the groupconsisting of alkyl, aryl, aralkyl, cycloalkyl, aralkoxycarbonyl,alkoxycarbonyl, and alkanoyl; or

[0162] (ii) two substituents such that the two substituents, togetherwith the aminoalkyl nitrogen, form a 5- to 8-member heterocyclyl orheteroaryl ring.

[0163] A prefix attached to a multi-component group only applies to thefirst component. To illustrate, the term “alkylcycloalkyl” contains twocomponents: alkyl and cycloalkyl. Thus, the C₁-C₆- prefix onC₁-C₆-alkylcycloalkyl means that the alkyl component of thealkylcycloalkyl contains from 1 to 6 carbon atoms; the C₁-C₆-prefix doesnot describe the cycloalkyl component. To illustrate further, the prefix“halo” on haloalkoxyalkyl indicates that only the alkoxy component ofthe alkoxyalkyl group is substituted with one or more halogen radicals.If halogen substitution may alternatively or additionally occur on thealkyl component, the group would instead be described as“halogen-substituted alkoxyalkyl” rather than “haloalkoxyalkyl.” Andfinally, if the halogen substitution may only occur on the alkylcomponent, the group would instead be described as “alkoxyhaloalkyl.”

[0164] If substituents are described as being “independently selected”from a group, each substituent is selected independent of the other.Each substituent therefore may be identical to or different from theother substituent(s).

[0165] When words are used to describe a substituent, therightmost-described component of the substituent is the component thatis bound at the location of the replaced hydrogen. To illustrate,benzene substituted with methoxyethyl has the following structure:

[0166] As can be seen, the ethyl is bound to the benzene, and themethoxy is the component of the substituent that is the componentfurthest from the benzene. As further illustration, benzene substitutedwith cyclohexanylthiobutoxy has the following structure:

[0167] When words are used to describe a linking element between twoother elements of a depicted chemical structure, the rightmost-describedcomponent of the substituent is the component that is bound to the leftelement in the depicted structure. To illustrate, if the chemicalstructure is X-L-Y and L is described as methylcyclohexanylethyl, thechemical would be X-ethyl-cyclohexanyl-methyl-Y.

[0168] When a chemical formula is used to describe a substituent, thedash on the left side of the formula indicates the portion of thesubstituent that is bound at the location of the replaced hydrogen. Toillustrate, benzene substituted with —C(O)—OH has the followingstructure:

[0169] When a chemical formula is used to describe a linking elementbetween two other elements of a depicted chemical structure, theleftmost dash of the substituent indicates the portion of thesubstituent that is bound to the left element in the depicted structure.The rightmost dash, on the other hand, indicates the portion of thesubstituent that is bound to the right element in the depictedstructure. To illustrate, if the depicted chemical structure is X-L-Yand L is described as —C(O)—N(H)—, the chemical would be:

[0170] The term “pharmaceutically acceptable” is used adjectivally inthis patent to mean that the modified noun is appropriate for use as apharmaceutical product or as a part of a pharmaceutical product.

[0171] With reference to the use of the words “comprise” or “comprises”or “comprising” in this patent (including the claims), Applicants notethat unless the context requires otherwise, those words are used on thebasis and clear understanding that they are to be interpretedinclusively, rather than exclusively, and that Applicants intend each ofthose words to be so interpreted in construing this patent, includingthe claims below.

EXAMPLES

[0172] The following examples are merely illustrative, and not intendedto be limiting to the remainder of this disclosure in any way.

[0173] Abbreviations are often used for reagents and solvents in thespecific examples that follow. Those abbreviations include thefollowing:

[0174] BOC=t-butoxycarbonyl

[0175] DEAD=diethyl azodicarboxylate

[0176] DMF=dimethylfonmamide

[0177] DMPU=1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone

[0178] EtOAc=ethyl acetate

[0179] EDC=1-ethyl-3-[3-(dimethylamino)-propyl]carbodiimidehydrochloride

[0180] Et₂O=diethyl ether

[0181] HOBT=1-hydroxybenzotriazole

[0182] MeOH=methanol

[0183] MeCl₂=methylene chloride

[0184] MsCl=methanesulfonyl chloride

[0185] NMM=N-methyl morpholine

[0186] THF=tetrahydrofruan

[0187] TsCl=toluenesulfonyl chloride

[0188] THP-O-hydroxylamine=O-tetrahydropyran-hydroxylamine andO-tetrahydro-2H-pyran-2-yl-hydroxylamine

[0189] The preparation of compounds useful in the synthesis of compoundsof the invention are provided herein below in Preparative Examples Ithrough XI.

Preparative Example I Preparation of 1,1-dimethylethyl ester4-[(hydroxyamino)-carbonyl]-4-[(phenoxyphenyl)-sulfonyl]-1-piperidinecarboxylicacid

[0190]

[0191] Part A: A solution of 4-(phenoxy)benzenethiol (2.03 g, 10.0 mmol)in DMSO (DMSO; 20 mL) was heated to 65° C. for 5 hr. The solutionremained at ambient temperature for 18 hr. The solution was extractedwith ethyl acetate and the combined organic layers were washed with H₂Oand saturated NaCl and dried over magnesium sulfate. Concentration invacuo provided the disulfide as a yellow oil (2.3 g, quantitativeyield).

[0192] Part B: To a solution of ethyl isonipecotate (15.7 g, 0.1 mol) inTHF (100 mL) was added a solution of di-tert-butyl dicarbonate (21.8 g,0.1 mol) in THF (5 mL) drop-wise over 20 min. The solution was stirredovernight (about 18° C.) at ambient temperature and concentrated invacuo to yield a light oil. The oil was filtered through silica gel (7:3ethyl acetate/hexanes) and concentrated in vacuo to give theBOC-piperidine compound (26.2 g, quantitative yield) as a clear,colorless oil.

[0193] Part C: To a solution of diisopropylamine (2.8 mL, 20 mmoL) inTHF (30 mL), cooled to −78° C., was added n-butyl lithium (12.5 mL, 20mmol) drop-wise. After 15 min, the BOC-piperidine compound of part B(2.6 g, 10 mmol) in THF (10 mL) was added drop-wise. After 1.5 hr, thesolution was cooled to −60° C. and the disulfide of part A (2.0 g, 10mmol) in THF (7 mL). The solution was stirred at ambient temperature for2 hr. The solution was diluted with H₂O and extracted with ethylacetate. The organic layer was washed with H₂O and saturated NaCl anddried over magnesium sulfate. Chromatography (on silica, ethylacetate/hexane) provided the sulfide as an oil (1.8 g, 40%).

[0194] Part D: To a solution of the sulfide of part C (1.8 g, 3.95 mmol)in dichloromethane (75 mL) cooled to 0° C., was added m-chloroperbenzoicacid (1.7 g, 7.9 mmol). The solution was stirred for 1.5 hr followed bydilution with H₂O and extraction with dichloromethane. The organic layerwas washed with 10 percent Na₂SO₄, H₂O, and saturated NaCl and driedover magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane)provided the sulfone as a solid (1.15 g, 59%).

[0195] Part E: To a solution of the sulfone of part D (800 mg, 1.63mmol) in THF (9 mL) and ethanol (9 mL) was added NaOH (654 mg, 16.3mmol) in H₂O (3 mL). The solution was heated at 65° C. for 18 hr. Thesolution was concentrated in vacuo and the residue was dissolved in H₂O.Following acidification with 2N HCl to pH 4, the solution was extractedwith ethyl acetate and the organic layer was washed with saturated NaCland dried over magnesium sulfate. Concentration in vacuo provided theacid as a white foam (790 mg, quantitative yield). Analytical calculatedfor C₂₃H₂₇NO₇S: C, 59.86; H, 5.90; N, 3.04; S, 6.95. Found: C, 59.49; H,6.37; N, 2.81; S, 6.59.

[0196] Part F: To a solution of the acid of part G (730 mg, 1.58 mmol)in DMF (9 mL) was added HOBT (256 mg, 1.90 mmol) followed by EDC (424mg, 2.21 mmol), 4-methylmorpholine (0.521 mL, 4.7 mmol) and 50 percentaqueous hydroxylamine (1.04 mL, 15.8 mmol). The solution was stirred for20 hr and additional N-hydroxybenzotriazole.H₂O (256 mg), EDC (424 mg)and 50 percent aqueous hydroxylamine (1.04 mL) were added. After anadditional 24 hr of stirring, the solution was diluted with H₂O andextracted with ethyl acetate and the organic layer was washed withsaturated NaCl and dried over magnesium sulfate. Reverse phasechromatography (on silica, acetonitrile/H₂O) provided the title compoundas a white solid (460 mg, 61%). HPLC purity: >99%. Analytical calculatedfor C₂₃H₂₈N₂O₇S: C, 57.97; H, 5.92; N, 5.88; S, 6.73. Found: C, 57.95;H, 6.02; N, 5.81; S, 6.85.

Preparative Example II Preparation ofN-hydroxy-4-[[4-(phenylthio)phenyl]sulfonyl]-1-(2-propynyl)-4-piperidinecarboxamide,monohydrochloride

[0197]

[0198] Part A: To a solution of ethyl isonipecotate (15.7 g, 0.1 mol) inTHF (100 mL) was added a solution of di-tert-butyl dicarbonate (21.8 g,0.1 mol) in THF (5 mL) drop-wise over 20 min. The solution was stirredovernight (about 18 hr) at ambient temperature and concentrated in vacuoto yield a light oil. The oil was filtered through silica gel (ethylacetate/hexanes) and concentrated in vacuo to give the BOC-piperidinecompound as a clear, colorless oil (26.2 g, quantitative yield).

[0199] Part B: A solution of 4-fluorothiophenol (50.29 g, 390 mmol) inDMSO (500 mL) was heated to 65° C. for 6 hr. The reaction was quenchedinto wet ice and the resulting solid was collected by vacuum filtrationto provide the disulfide as a white solid (34.4 g, 68.9%).

[0200] Part C: To a solution of the BOC-piperdine compound of part A (16g, 62 mmol) in THF (300 mL) cooled to minus 50° C. was added lithiumdiisopropylamide (41.33 mL, 74 mmol) and the solution was stirred for1.5 hr at 0° C. To this solution was added the disulfide of part B(15.77 g, 62 mmol), and the resulting solution was stirred at ambienttemperature for 20 hr. The reaction was quenched with the addition ofH₂O and the solution was concentrated in vacuo. The aqueous residue wasextracted with ethyl acetate and the organic layer was washed with 0.5NKOH, H₂O, and saturated NaCl. Chromatography (on silica, hexane/ethylacetate) provided the sulfide as an oil (18.0 g, 75%).

[0201] Part D: To a solution of the sulfide of part C (16.5 g, 43 mmol)in dichloromethane (500 mL) cooled to 0° C. was added 3-chloroperbenzoicacid (18.0 g, 86 mmol) and the solution was stirred for 20 hr. Thesolution was diluted with H₂O and extracted with dichloromethane. Theorganic layer was washed with 10 percent Na₂SO₃, H₂O, and saturated NaCland dried over magnesium sulfate. Chromatography (on silica, ethylacetate/hexane) provided the sulfone as a solid (10.7 g, 60%).

[0202] Part E: Into a solution of the sulfone of part D (10 g, 24.0mmol) in ethyl acetate (250 mL) was bubbled HCl gas for 10 min followedby stirring at ambient temperature for 4 hr. Concentration in vacuoprovided the amine hydrochloride salt as a white solid (7.27 g, 86%).

[0203] Part F: To a solution of the amine hydrochloride salt of part E(5.98 g, 17.0 mmol) in DMF (120 mL) was added potassium carbonate (4.7g, 34.0 mmol) followed by propargyl bromide (2.02 g, 17.0 mmol) and thesolution was stirred for 4 hr at ambient temperature. The solution waspartitioned between ethyl acetate and H₂O, and the organic layer waswashed with H₂O and saturated NaCl and dried over magnesium sulfate.Chromatography (on silica, ethyl acetate/hexane) provided the propargylamine as a yellow oil (5.2 g, 86%).

[0204] Part G: To a solution of the propargyl amine of part F in DMF (15mL) was added thiophenol (0.80 mL, 7.78 mmol) and CsCO₃ (2.79 g, 8.56mmol) and the solution was heated to 70° C. for 6 hr. The solution waspartitioned between ethyl ether and H₂O. The organic layer was washedwith H₂O and saturated NaCl, and dried over magnesium sulfate.Chromatography (on silica, ethyl acetate/hexane) provided theS-phenoxyphenyl compound as an oil (1.95 g, 56%).

[0205] Part H: To a solution of the S-phenoxyphenyl of part G (1.81 g,4.06 mmol) in ethanol (21 mL) and H₂O (3.5 mL) was added KOH (1.37 g,24.5 mmol) and the solution was heated to 105° C. for 4.5 hr. Thesolution was acidified to a pH value of 1 with concentrated HCl solutionand then concentrated to provide the acid as a yellow residue that wasused without additional purification (1.82 g).

[0206] Part I: To a solution of the acid of part H (1.82 g, 4.06 mmol)in acetonitrile (20 mL) was addedO-tetrahydro-2H-pyran-2-yl-hydroxylamine (723 mg, 6.17 mmol) andtriethylamine (0.67 mL, 4.86 mmol). To this stirring solution was addedEDC (1.18 g, 6.17 mmol) and the solution was stirred for 18 hr. Thesolution was partitioned between H₂O and ethyl acetate. The organiclayer was washed with H₂O, saturated NaHCO₃ and saturated NaCl and driedover magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane)provided the protected hydroxamate as a white solid (1.32 g, 63%).

[0207] Part J: To a solution of the protected hydroxamate of part 1(9.65 g, 18.7 mmol) in methanol (148 mL) cooled to 0° C. was addedacetyl chloride (4.0 mL, 56.2 mmol), and the solution was stirred for 45min at ambient temperature. Concentration in vacuo followed bytrituration with ethyl ether provided the title compound as a whitesolid (8.10 g, 94%). MS(CI) MH⁺ calculated for C₂₁H₂₂N₂O₄S₂: 431, found431.

Preparative Example III Preparation ofN-hydroxy-4-[(4-phenoxyphenyl)sulfonyl]-1-(2-propynyl)-4-piperidinecarboxamide,monohydrochloride

[0208]

[0209] Part A: A solution of 4-(phenoxy)benzenethiol (2.03 g, 10.0 mmol)in DMSO (20 mL) was heated to 65° C. for 5 hr. The solution remained atambient temperature for 18 hr. The solution was extracted with ethylacetate and the combined organic layers were washed with H₂O andsaturated NaCl, and dried over magnesium sulfate. Concentration in vacuoprovided the disulfide as a yellow oil (2.3 g, quantitative yield).

[0210] Part B: To a solution of ethyl isonipecotate (15.7 g, 0.1 mol) inTHF (100 mL) was added a solution of di-tert-butyl dicarbonate (21.8 g,0.1 mol) in THF (5 mL) dropwise over 20 min. The solution was stirredovernight at ambient temperature and concentrated in vacuo to yield alight oil. The oil was filtered through silica gel (ethylacetate/hexane) and concentrated in vacuo to give the BOC-piperidinecompound as a clear, colorless oil (26.2 g, quantitative yield).

[0211] Part C: To a solution of diisopropylamine (2.8 mL, 20 mmoL) inTHF (30 mL), cooled to −78° C., was added n-butyl lithium (12.5 mL, 20mmol) dropwise. After 15 min, the BOC-piperidine compound of Part B (2.6g, 10 mmol) in THF (10 mL) was added dropwise. After 1.5 hr, thesolution was cooled to −60° C. and the disulfide of Part A (2.0 g, 10mmol) in THF (7 mL) was added. The solution was stirred at ambienttemperature for 2 hr. The solution was diluted with H₂O and extractedwith ethyl acetate. The organic layer was washed with H₂O and saturatedNaCl and dried over magnesium sulfate. Chromatography (on silica, ethylacetate/hexane) provided the sulfide as an oil (1.8 g, 40%).

[0212] Part D: To a solution of the sulfide of Part C (1.8 g, 3.95 mmol)in dichloromethane (75 mL) cooled to 0° C., was added m-chloroperbenzoicacid (1.7 g, 7.9 mmol). The solution was stirred for 1.5 hr followed bydilution with H₂O and extraction with dichloromethane. The organic layerwas washed with 10 percent Na₂SO₄, H₂O, and saturated NaCl and driedover magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane)provided the sulfone as a solid (1.15 g, 59%).

[0213] Part E: Into a solution of the sulfone of Part D (3.56 g, 7.0mmol) in ethyl acetate (100 mL) cooled to 0° C. was bubbled HCl gas for5 min. Concentration in vacuo followed by trituration with ethyl etherprovided the amine hydrochloride salt as a white solid (3.5 g,quantitative yield). MS(CI) MH⁺ calculated for C₂₀H₂₃NO₅S: 390, found390.

[0214] Part F: To a solution of the amine hydrochloride salt of part E(2.6 g, 6 mmol) and K₂CO₃ (1.66 g, 12 mmol) in DMF (50 mL) was addedpropargyl bromide (892 mg, 6 mmol) and the solution was stirred atambient temperature for 4 hr. The solution was diluted with H₂O andextracted with ethyl acetate. The combined organic layers were washedwith saturated NaCl and dried over magnesium sulfate. Chromatography (onsilica, ethyl acetate/hexane) provided the propargyl amine as a whitesolid (2.15 g, 82%).

[0215] Part G: To a solution of the propargyl amine of part F (2.15 g, 5mmol) in THF (30 mL) and ethanol (30 mL) was added NaOH (2.0 g, 50 mmol)and the solution was heated at 65° C. for 48 hr. The solution wasconcentrated in vacuo and the aqueous residue was acidified to a pHvalue of 5. Vacuum filtration of the resulting precipitate provided theacid as a white solid (2.04 g, quantitative yield).

[0216] Part H: To a solution of the acid of part G (559 mg, 1.4 mmol) indichloromethane (5 mL) was added triethylamine (0.585 mL, 4.2 mmol) and50 percent aqueous hydroxylamine (0.925 mL, 14.0 mmol) followed bybromotris(pyrrolidino)phosphonium hexafluourphosphate (PyBroP®; 718 mg,1.54 mmol). The solution was stirred at ambient temperature for 4 hr.The solution was diluted with H₂O and extracted with dichloromethane.The organic layer was washed with saturated NaCl and dried overmagnesium sulfate. Reverse phase chromatography (on silica,acetonitrile/H₂O) provided the hydroxamate as a white solid (140 mg,25%). Analytical calculation for C₂₁H₂₂N₂O₅S: C, 60.85; H, 5.37; N,6.76; S, 7.74. Found: C, 60.47; H, 5.35; N, 6.61; S, 7.46.

[0217] Part I: To a solution of the hydroxamate of part H (121 mg, 0.292mmol) in methanol (2 mL) cooled to 0° C. was added acetyl chloride(0.228 mL, 0.321 mmol) in methanol (1 mL). After stirring at ambienttemperature for 30 min, the solution was concentrated under a stream ofN₂. Trituration with ethyl ether provided the title compound as a whitesolid (107 mg, 81%). Analytical calculation for C₂₁H₂₂N₂O₅S.HCl.0.3H₂O:C, 55.27; H, 5.21; N, 6.14. Found: C, 54.90; H, 5.37; N, 6.07.

Preparative Example IV Preparation of4-[(4-fluorophenyl)sulfonyl]tetrahydro-N-[(tetrahydro-2H-pyran-2-yl)oxy]-2H-pyran-4-carboxamide

[0218]

[0219] Part A: In dry equipment under nitrogen, sodium metal (8.97 g,0.39 mol) was added to methanol (1000 mL) at 2° C. The reaction wasstirred at ambient temperature for 45 min, at which time the sodium haddissolved. The solution was chilled to 5° C. and p-fluorothiophenol(41.55 mL, 0.39 mmol) was added, followed by methyl 2-chloroacetate(34.2 mL, 0.39 mol). The reaction was stirred at ambient temperature for4 hr, filtered, and concentrated in vacuo to give the sulfide as a clearcolorless oil (75.85 g, 97%).

[0220] Part B: To a solution of the sulfide from part A (75.85 g, 0.38mol) in methanol (1000 mL) were added water (100 mL) and Oxone® (720 g,1.17 mol) at 20° C. An exotherm to 67° C. was noted. After 2 hr, thereaction was filtered and the cake was washed well with methanol. Thefiltrate was concentrated in vacuo. The residue was taken up in ethylacetate and washed with brine, dried over MgSO₄, filtered, andconcentrated in vacuo to give the sulfone as a crystalline solid (82.74g, 94%).

[0221] Part C: To a solution of the sulfone from part B (28.5 g, 0.123mol) in N,N-dimethylacetamide (200 mL) were added potassium carbonate(37.3 g, 0.27 mol), bis-(2-bromoethyl)ether (19.3 mL, 0.147 mol),4-dimethylaminopyridine (0.75 g, 6 mmol), and tetrabutylammonium bromide(1.98 g, 6 mmol). The reaction was stirred overnight (about 18 hr) atambient temperature. The reaction was slowly poured into 1N HCl (300mL), the resultant solid filtered and the cake washed well with hexanes.The solid was recrystallized from ethyl acetate/hexanes to give thepyran compound as a beige solid (28.74 g, 77%). MS (ES+) MH+ calculatedfor C₁₃H₁₅O₅S₁F₁: 303, found 303.

[0222] Part D: In dry equipment under nitrogen, the pyran compound frompart C (8.0 g, 26.5 mmol) was dissolved in dry tetrahydrofuran (250 mL)and a solution of potassium trimethylsilonate (10.2 g, 79.5 mmol) in drytetrahydrofuran (15 mL) was added at ambient temperature. After 90 min,water (100 mL) was added and the solution concentrated in vacuo. Theresidue was taken up in water and extracted with ethyl acetate to removeunreacted starting material. The aqueous solution was treated with 6NHCl until pH═I. The slurry was extracted with ethyl acetate and thecombined extracts washed with water, dried over Na₂SO₄, filtered, andconcentrated in vacuo. The residue was heated in diethyl ether, thesolid filtered and dried to give the carboxylic acid as a crystallinesolid (5.78 g, 76%). HRMS (ES−) M−H calculated for C₁₂H₁₃O₅S₁F₁: 287.04,found 287.04.

[0223] Part E: In dry equipment under nitrogen, the carboxylic acid frompart D (9.1 g, 31.6 mmol) was dissolved in dry N,N-dimethylformamide (70mL) and the remaining reagents were added to the solution in thefollowing order: N-hydroxybenzotriazole hydrate (5.1 g, 37.9 mmol),N-methylmorpholine (10.4 mL, 94.8 mmol),O-tetrahydro-2H-pyran-2-yl-hydroxylamine (11.5 g, 98 mmol), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.48 g,44.2 mmol). After 3 hr at ambient temperature, the reaction wasconcentrated in vacuo. The residue was taken up in ethyl acetate, washedwith water, 5% KHSO₄, saturated NaHCO₃, brine, dried over Na₂SO₄,filtered, and concentrated in vacuo. Chromatography (on silica, ethylacetate/hexanes) provided the title compound as a crystalline solid (9.7g, 80%). HRMS (ES+) MH+ calculated for C₁₇H₂₂NO₆S₁F₁: 388.12, found388.12.

Preparative Example V Preparation oftetrahydro-N-hydroxy-4-[[4-[4-trifluoromethoxy)-phenoxy)phenyl]sulfonyl]-2H-pyran-4-carboxamide

[0224]

[0225] Part A: To a solution of the title compound of PreparativeExample TV (3.1 g, 8 mmol) in N,N-dimethylacetamide (20 mL) were addedcesium carbonate (8.8 g, 27 mmol) and p-(trifluoromethoxy)phenol (2.1mL, 16 mmol). The slurry was stirred at 95° C. for 19 hr. The reactionwas concentrated in vacuo. The residue was taken up in ethyl acetate,washed with brine, dried over Na₂SO₄, filtered, and concentrated invacuo. Chromatography (on silica, ethyl acetate/hexanes) provided thesubstituted THP-protected hydroxamate as a white foam (4.2 g, 96%). HRMS(ES+) MH+ calculated for C₂₄H₂₆N₁O₈S₁F₃: 546.14, found 546.14.

[0226] Part B: To a slurry of the THP-protected hydroxamate from part A(4.0 g, 7.3 mmol) in dioxane (20 mL) were added a 4N HCl dioxanesolution (20 mL) and methanol (20 mL). After 15 min, at ambienttemperature, the reaction was diluted with ethyl acetate and washed withwater, dried over Na₂SO₄, filtered, and concentrated in vacuo. Theproduct was recrystallized (acetone/hexanes) to give the title compoundas a white solid (2.2 g, 65%). HRMS (ES+) M+NH₄ ⁺ calculated forC₁₉H₁₈N₁O₇S₁F₃: 479.11, found 479.11.

Preparative Example VI Preparation of1-cyclopropyl-N-hydroxy-4-[[4-(2-phenoxy-ethoxy)phenyl]sulfonyl]-4-piperidinecarboxamide, monohydrochloride

[0227]

[0228] Part A: To a solution of the product of Preparative Example II,part E, (14.36 g, 40 mmol) in methanol (50 mL) was added acetic acid(24.5 g, 400 mmol), a portion (about 2 g) of 4-Angstrom molecularsieves, (1-ethoxycyclopropyl)-oxytrimethyl silane (25.8 mL, 148 mmol)and sodium cyanoborohydride (7.05 g, 112 mmol). The solution was heatedat reflux for 8 hr. The precipitated solids were removed by filtrationand the filtrate was concentrated in vacuo. The residue was diluted withH₂O (400 mL) and extracted with ethyl acetate. The organic layer waswashed with saturated NaCl and dried over MgSO₄, filtered andconcentrated in vacuo. The solid was filtered, washed with H₂O/diethylether to give the desired cyclopropyl amine {ethyl4-[(4-fluorophenyl-sulfonyl)]-1-cyclopropyl-4-piperidinecarboxylate} asa white solid (11.83 g, 81.5%). MS MH⁺ calculated for C₁₇H₂₂NO₄SF: 356,found: 356.

[0229] Part B: A solution of the cyclopropyl amine of Part A (2.0 g, 5.6mmol), ethylene glycol phenyl ether (2.8 mL, 23 mmol), and cesiumcarbonate (7.3 g, 23 mmol) in DMAC (10 mL) was heat at 125-135° C. for18 hr under an atmosphere of nitrogen. The mixture was concentrated invacuo, diluted with water, and extracted with ethyl acetate. Thecombined ethyl acetate layers were washed with water and brine, driedover magnesium sulfate, concentrated in vacuo, dissolved in diethylether, precipitated as the hydrochloride salt, and dried at 40° C. in avacuum oven. The solid was dissolved into a mixture of water,acetonitrile, and ethanol and then the pH was adjusted to 12 with 1NNaOH solution. The mixture was concentrated in vacuo to remove ethanoland acetonitrile. The solid was isolated by filtration, washed withwater, and dried at 50° C. in a vacuum oven to afford the ether as awhite solid (1.8 g, 68%): MS+ calcd. for C₂₅H₃₁NO₆S 474, found 474.Anal. calcd. for C₂₅H₃₁NO₆S: C, 63.40; H, 6.60; N, 2.96; S, 6.77. Found:C, 63.35; H, 6.59; N, 2.99; S, 6.61.

[0230] Part C: A mixture of the ether of part B (1.8 g, 3.7 mmol) and a50% NaOH aqueous solution (3.0 g, 37 mmol) in THF (32 mL), EtOH (32 mL),and H₂O (16 mL) was heated at 60° C. under a N₂ atmosphere for 24 hr.The material was concentrated in vacuo and triturated with diethyl etherto give a solid. The tan solid was dissolved into a mixture of water,ethanol, and THF, precipitated by adjusting the pH to 3 withconcentrated hydrochloric acid, concentrated in vacuo, triturated withwater, and dried at 50° C. in a vacuum oven to give a crude white solidacid (2.3 g).

[0231] A mixture of the crude white solid acid (2.3 g),N-hydroxybenzotriazole (1.9 g, 14 mmol), 4-methylmorpholine (1.6 mL, 14mmol), O-tetrahydro-2H-pyran-2-yl-hydroxylamine (1.1 g, 9.4 mmol), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.7 g, 14mmol) in DMF (90 mL) was stirred at ambient temperature under a nitrogenatmosphere for 2 days. The mixture was concentrated in vacuo, dilutedwith water, and extracted with ethyl acetate. The organic layer waswashed with 1N NaOH solution, water, and brine, dried over magnesiumsulfate, concentrated in vacuo, and purification by flash chromatography(20:80 to 40:60 ethyl acetate/toluene) to afford the protectedhydroxamate as a white solid: (0.43 g, 21%): MS MH+ calcd. forC₂₈H₃₆N₂O₇S 545, found 545. Anal. calcd. for C₂₈H₃₆N₂O₇S: C, 61.74; H,6.66; N, 5.14; S, 5.89. Found: C, 61.72; H, 6.75; N, 5.06; S, 5.91.

[0232] Additional compound was isolated by acidifying the aqueous layerto pH of 3, collecting the solid by filtration, and drying to give awhite solid (0.80 g).

[0233] Part D: To an ambient temperature solution of acetyl chloride(0.31 mL, 4.4 mmol) in methanol (11 mL) under a nitrogen atmosphere wasadded the protected hydroxamate of part C (0.80 g, 1.5 mmol). Afterstirring for 2.5 hr, the precipitate was collected by filtration, washedwith diethyl ether, and dried at 45° C. in a vacuum oven to afford thetitle compound as a white solid (0.58 g, 79%): MS MH+ calcd. forC₂₃H₂₈N₂O₆S 461, found 461. Anal. calcd. for C₂₃H₂₈N₂O₆S.1.5HCl: C,53.62; H, 5.77; N, 5.44; S, 6.22. Found: C, 53.47; H, 5.79; N, 5.41; S,6.16.

Preparative Example VII Preparation ofN-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-(trifluoro-methoxy)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamide,monohydrochloride

[0234]

[0235] Part A: To a solution of the product of Preparative Example II,Part D (30 g, 161 mmol) in dichloromethane (50 mL) cooled to 0° C. wasadded trifluroacetic acid (25 mL) and the solution was stirred atambient temperature for 1 hr. Concentration in vacuo provided the aminetrifluoroacetate salt as a light yellow gel. To the solution of thetrifluoroacetate salt and K₂CO₃ (3.6 g, 26 mmol) inN,N-dimethylformamide (50 mL) cooled to 0° C. was added 2-bromoethylmethyl ether (19 mL, 201 mmol), and solution was stirred at ambienttemperature for 36 hr. Then, N,N-dimethylformamide was evaporated underhigh vacuum and the residue was diluted with ethyl acetate. The organiclayer was washed with water and dried over MgSO₄. Concentration in vacuoprovided the methoxyethyl amine as a light yellow gel (26.03 g, 86.8%).

[0236] Part B: To a solution of methoxyethyl amine (6.0 g, 16.0 mmol) ofPart A and powdered K₂CO₃ (4.44 g, 32 mmol) in N,N-dimethylformamide (30mL) was added 4-(trifluoromethoxy)phenol (5.72 g, 32 mmol) at ambienttemperature and the solution was heated to 90° C. for 25 hr. Thesolution was concentrated under high vacuum and the residue wasdissolved in ethyl acetate. The organic layer was washed with 1N NaOH,H₂O and dried over MgSO₄. Chromatography on silica eluting with ethylacetate/hexane provided trifluoromethoxy phenoxyphenyl sulfone as alight yellow gel (7.81 g, 91.5%).

[0237] Part C: To a solution of trifluoromethoxy phenoxyphenyl sulfoneof Part B (7.81 g, 14.7 mmol) in ethanol (14 mL) and tetrahydrofuran (14mL) was added NaOH (5.88 g, 147 mmol) in H₂O (28 mL) from an additionfunnel at ambient temperature. The solution was then heated to 60° C.for 18 hr. The solution was concentrated in vacuo and diluted withwater. The aqueous layer was extracted with ether and acidified to pH=2.Vacuum filtration of white precipitation provided the acid as a whitesolid (5.64 g, 73.3%).

[0238] Part D: To a solution of the acid of Part C (5.64 g, 10.8 mmol),N-methyl morpholine (4.8 mL, 43.1 mmol), 1-hydroxybenzotriazole (4.38 g,32.4 mmol) and O-tetrahydropyranyl hydroxylamine (2.5 g, 21.6 mmol) inN,N-dimethylformamide (50 mL) was added1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (6.2 g,32.4 mmol), and the solution was stirred at ambient temperature for 24hr. The solution was concentrated under high vacuum and the residue wasdissolved in ethyl acetate. The organic layer was washed with saturatedaqueous NaHCO₃, H₂O and dried over MgSO₄. Concentration in vacuo andchromatography on silica eluting with ethyl acetate/hexane provided thetetrahydropyranyl-protected hydroxamate as a white foam (6.65 g,quantitative yield).

[0239] Part E: To a solution of 4N HCl in dioxane (28 mL, 110 mmol) wasadded a solution of the tetrahydropyranyl-protected hydroxamate of PartD (6.65 g, 11.03 mmol) in methanol (3 mL) and dioxane (9 mL) and wasstirred at ambient temperature for 3 hr. Concentration in vacuo andtrituration with diethyl ether provided the title compound as a whitesolid (4.79 g, 78.2%). Analytical calculation forC₂₂H₂₅N₂O₇SF₃.HCl.0.5H₂O: C, 46.85; H, 4.83; N, 4.97; S, 5.69. Found: C,46.73; H, 4.57; N, 4.82; S, 5.77.

Preparative Example VIII Preparation ofN-hydroxy-1-[2-(4-morpholinyl)-ethyl]-4-[[4-[4-(trifluoromethyl)phenoxy]-phenyl]sulfonyl]-4-piperidinecarboxamide,dihydrochloride

[0240]

[0241] Part A: To a suspension of 4-bromopiperidine hydrobromide (107.0g, 0.436 mol) in tetrahydrofuran (1 L) was slowly added triethylamine(122 mL, 0.872 mol) followed by di-tert-butyl dicarbonate (100 g, 0.458mol), which was added in several portions. The resulting mixture wasstirred at ambient temperature for 22 hr then filtered and concentratedin vacuo. The solids were washed with hexanes and then collected byfiltration to give the Boc-piperidine compound as an amber oil (124 g,>100%).

[0242] Part B: To a solution of 4-fluorophenol (50.0 g, 0.390 mol) inacetone (400 mL), degassed with N₂, was added Cs₂CO₃ (159 g, 0.488 mol).After degassing the resulting mixture with N₂ for 5 min, theBoc-piperidine compound of Part A (85.9 g, 0.325 mol) was added. Theresulting mixture was stirred at ambient temperature for 18 hr and thenfiltered through a pad of Celite®, washing with acetone. The filtratewas concentrated in vacuo to provide the sulfide as a tan residue (98.5g, 97%).

[0243] Part C: To a solution of the sulfide of Part B (8.00 g, 25.7mmol) in dichloromethane (90 mL) and methanol (15 mL) was addedmonoperoxyphthalic acid magnesium salt hexahydrate (19.1 g, 38.6 mmol)in two portions. The resulting mixture was stirred at ambienttemperature for 1.5 hr and then filtered. The filtrate was washed withsaturated NaHCO₃ and then with saturated NaCl. The combined aqueouslayers were extracted with dichloromethane (100 mL). The combinedorganic layers were dried over Na₂SO₄ and then concentrated in vacuo.The resulting solids were washed with hexanes then dissolved indichloromethane and filtered through a pad of Celite®, washing withdichloromethane. The filtrate was concentrated in vacuo andrecrystallization from ethyl acetate provided the sulfone as a whitecrystalline solid (4.45 g, 50%).

[0244] Part D: To a solution of sulfone of Part C (7.00 g, 20.4 mmol) inN,N-dimethylformamide (40 mL) was added Cs₂CO₃ (19.9 g, 61.2 mmol) andα,α,α-trifluoro-p-cresol (3.97 g, 24.5 mmol). The resulting mixture washeated at 80° C. for 16 hr. After cooling to ambient temperature, thereaction mixture was concentrated in vacuo. The resulting residue wastreated with H₂O and the solids were collected by filtration. The solidswere then washed with hexanes then methanol to provide the biaryl etheras a tan solid (8.60 g, 87%).

[0245] Part E: To a solution of the biaryl ether of Part D (8.59 g, 17.7mmol) in tetrahydrofuran (100 mL), cooled to 0° C., was slowly addedlithium bis(trimethylsilyl)amide (22.0 mL, 11.0M in tetrahydrofuran,22.0 mmol), at such a rate that the temperature of the reaction neverexceeded 1° C. The resulting mixture was stirred at 0° C. for 1 hr thena solution of methyl chloroformate (2.05 mL, 26.6 mmol) intetrahydrofuran (5.0 mL) was slowly added, at such a rate that thetemperature of the reaction mixture never exceeded 4° C. After theaddition was complete, the mixture was slowly permitted to warm toambient temperature. Saturated NH₄Cl (50 mL) was added and thetetrahydrofuran was removed in vacuo. Water (50 mL) was added to theresidue which was then extracted with ethyl acetate. The combinedorganic layers were washed with saturated NaCl and dried over Na₂SO₄.Recrystallization from methanol provided the methyl ester as a paleyellow crystalline solid (7.66 g, 80%).

[0246] Part F: To a solution of the methyl ester of Part E (7.66 g, 14.1mmol) in dioxane (30 mL) and methanol (10 mL) was added a solution of 4NHCl in dioxane (10 mL, 40 mmol). After stirring at ambient temperaturefor 2 hr, additional 4N HCl in dioxane (10 mL, 40 mmol) was added. Afterstirring at ambient temperature for 2.5 hr, the reaction mixture wasconcentrated in vacuo to provide the amine as an off-white solid (6.80g, >100%).

[0247] Part G: To a suspension of the amine of Part F (3.00 g, 6.25mmol) in acetonitrile (20 mL) was added K₂CO₃ (3.46 g, 25.0 mmol),4-(2-chloroethyl)morpholine hydrochloride (1.22 g, 6.56 mmol) and acatalytic amount of NaI. The resulting mixture was heated at reflux for22 hr. After cooling to ambient temperature, the reaction mixture wasfiltered through a pad of Celite®, washing with ethyl acetate. Thefiltrate was concentrated in vacuo to provide the morpholinyl ethylamine as a tan solid (3.45 g, >100%).

[0248] Part H: To a solution of the morpholinyl ethyl amine of Part G(3.45 g, 6.25 mmol) in tetrahydrofuran (60 mL) was added potassiumtrimethylsilanolate (1.60 g, 12.50 mmol). After stirring at ambienttemperature for 25 hr, H₂O was added. The reaction mixture was thenneutralized (pH 7) with 1N HCl. The tetrahydrofuran was removed in vacuoand the resulting precipitate was collected by filtration and washedwith diethyl ether to provide the amino acid as an off-white solid (2.87g, 85%).

[0249] Part I: To a suspension of the amino acid of Part H (2.87 g, 5.29mmol) in dichloromethane (25 mL) was added N-methylmorpholine (1.74 mL,15.9 mmol), O-(tetrahydropuranyl)hydroxylamine (0.682 g, 5.82 mmol) andPyBroP® (2.96 g, 6.35 mmol). After stirring at ambient temperature for19 hr, additional N-methylmorpholine (0.872 mL, 7.94 mmol),O-(tetrahydropuranyl) hydroxylamine (0.310 g, 2.65 mmol) and PyBroP®(1.48 g, 3.17 mmol) were added. The resulting mixture was stirred atambient temperature for 3 hr and then concentrated in vacuo. The residuewas partitioned between ethyl acetate and H₂O. The organic layers werewashed with saturated NaCl and dried over Na₂SO₄. Chromatography (onsilica, methanol/chloroform) provided the protected hydroxamate as anoff-white solid (2.62 g, 77%).

[0250] Part J: To a solution of the protected hydroxamate of Part I(2.62 g, 4.08 mmol) in dioxane (9 mL) and methanol (3 mL) was added asolution of 4N HCl in dioxane (10 mL, 40.0 mmol). The resulting mixturewas stirred at ambient temperature for 2 hr and then diethyl ether (20mL) was added. The resulting solids were collected by filtration to givethe title compound as an off-white solid (2.31 g, 90%). MS MH⁺calculated for C₂₅H₃₁O₆N₃SF₃: 558, found 558.

Preparative Example IX Preparation of1-cyclopropyl-N-hydroxy-4-[[4-[4-(trifluoromethoxy)phenoxy]-phenyl]sulfonyl]-4-piperidine-carboxamide,monohydrochloride

[0251]

[0252] Part A: To a solution of the product of Preparative Example VI,Part A, (6.97 g, 19.6 mmol) in DMF (500 mL) was added K₂CO₃ (3.42 g,18.0 mmol) and 4-(triflouromethoxy)phenol (3.7 g, 24.8 mmol). Thesolution was stirred at 90° C. for 40 hr. The solution was diluted withH₂O (600 mL) and extracted with ethyl acetate. The organic layer waswashed with water, saturated NaCl and dried over MgSO₄, filtered andconcentrated in vacuo to afford the desired diaryl ether as an oil (8.5g, quantitative). HRMS MH⁺ calculated for C₂₄H₂₆NSO₆F₃: 514.1511. Found514.1524.

[0253] Part B: To a solution of diaryl ether from Part A (8.4 g, 16.4mmol) in ethanol (50 mL) and tetrahydrofuran (50 mL) was added asolution of NaOH (6.54 g, 164 mmol) in water (20 mL) and the solutionwas heated at 60° C. for 18 hr. The solution was concentrated in vacuoto remove most of organic solvents and the aqueous residue was acidifiedto pH=4.0. The resulting precipitate was filtered to give the desiredfiltered to give the hydrochloride salt as a white solid (5.01 g, 63%).HRMS MH⁺ calculated for C₂₂H₂₂NSO₆F₃: 486.1198, found 486.1200.

[0254] Part C: To a solution of the hydrochloride salt of Part B (5.0 g,10.3 mmol) in DMF (80 mL) were added 1-hydroxybenzotriazole (1.65 g,12.3 mmol), N-methyl morpholine (3.4 mL, 30.9 mmol) andO-tetrahydropyranyl hydroxylamine hydrochloride (1.8 g, 15.4 mmol)followed by 1-3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride(1.60 g, 12.3 mmol). The solution was stirred at ambient temperature for42 hr. The solution was diluted with H₂O (400 mL) and extracted withethyl acetate. The organic layer was washed with saturated NaCl anddried over MgSO₄, filtered and concentrated in vacuo. Chromatography onsilica gel, eluting with 30% ethyl acetate/hexane provided the desiredtetrahydropyranyl-protected hydroxamate as a white solid (5.41 g, 89%).

[0255] Part D: To a solution of tetrahydropyranyl-protected hydroxamateof Part C (5.4 g, 9.2 mmol) in dioxane (80 mL) and methanol (20 mL) wasadded 4 N HCl/dioxane (50 mL). The reaction was stirred at ambienttemperature for 2.5 hr, the solution was concentrated in vacuo.Trituration with diethyl ether afforded the title compound as a whitesolid (4.02 g, 81%). HRMS MH⁺ calculated for C₂₂H₂₃N₂SO₆F₃: 501.1307,found 501.1324.

Preparative Example X Preparation of1-cyclopropyl-N-hydroxy-4-[[4-[4-(trifluoromethyl)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamide,monohydrochloride

[0256]

[0257] Part A: To a solution of the product of Preparative Example VI,Part A, (5.96 g, 15.0 mmol) in DMF (100 mL) was added K₂CO₃ (12.34 g,38.0 mmol) and

□-trifluoromethyl phenol (3.65 g, 22.5 mmol). The solution was stirred90° C. for 28 hr. The solution was diluted with H₂O (400 mL) andextracted with ethyl acetate. The organic layer was washed with water,saturated NaCl and dried over MgSO₄, filtered and concentrated in vacuoto afford desired aryl ether as an oil (7.54 g, quantitative)

[0258] Part B: To a solution of aryl ether from Part A (7.54 g, 15.0mmol) in ethanol (40 mL) and tetrahydrofuran (40 mL) was added asolution of NaOH (6.06 g, 151.0 mmol) in water (20 mL) and the solutionwas heated at 60° C. for 18 hr. The solution was concentrated in vacuoand the aqueous residue was acidified to pH=2.0. The resultingprecipitate was filtered to give the desired hydrochloride salt as awhite solid (7.98 g, quantitative). MS MH⁺ calculated for C₂₂H₂₂NSO₅F₃:470, found 470.

[0259] Part C: To a solution of the hydrochloride salt of Part B (7.60g, 15.0 mmol) in DMF (100 mL) were added 1-hydroxybenzotriazole (2.44 g,18.0 mmol), N-methyl morpholine (3.4 mL, 30.9 mmol) andO-tetrahydropyranyl hydroxylamine hydrochloride (2.63 g, 22.5 mmol)followed by 1-3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride(4.02 g, 21.0 mmol). The solution was stirred at ambient temperature for96 hr. The solution was diluted with H₂O (400 mL) and extracted withethyl acetate. The organic layer was washed with saturated NaCl anddried over MgSO₄, filtered and concentrated in vacuo. Chromatography onsilica eluting with 30% ethyl acetate/hexane provided the desiredtetrahydropyranyl-protected hydroxamate as a white solid (5.93 g, 69%).

[0260] Part D: To a solution of tetrahydropyranyl-protected hydroxamateof Part C (3.8 g, 6.7 mmol) in dioxane (100 mL) was added 4 NHCl/dioxane (30 mL). The reaction was stirred at ambient temperature for2 hr, then the solution was concentrated in vacuo. Trituration withdiethyl ether afforded the title compound as a white solid (3.33 g,96%). MS MH⁺ calculated for C₂₂H₂₃N₂SO₅F₃: 485, found 485.

Preparative Example XI Preparation of Resin II

[0261] Step 1: Attachment of Compound of Preparative Example IV to ResinI.

[0262] A 500 mL round-bottomed flask was charged with of resin I [Floydet al., Tetrahedron Lett. 1996, 37, 8045-8048] (8.08 g, 9.7 mmol) and1-methyl-2-pyrrolidinone (50 mL). A magnetic stirring bar was added, andthe resin slurry slowly stirred. A separate solution of the compound ofPart D, Preparative Example IV (5.58 g, 19.4 mmol) in1-methyl-2-pyrrolidinone (35 mL) was added to the slurry followed byaddition of benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphoniumhexafluorophosphate (10.1 g, 19.4 mmol) in one portion. Once thehexafluorophosphate salt had dissolved, 4-methylmorpholine (4.26 mL, 39mmol) was added dropwise. The reaction slurry was stirred at roomtemperature for 24 hr, then the resin was collected in a sintered-discfunnel and washed with N,N-dimethylformamide, methanol, methylenechloride and diethyl ether (3×30 mL each solvent). The resin was driedin vacuo to yield 10.99 g polymer-bound hydroxymate as a tan polymericsolid. Theoretical loading on polymer was 0.91 mmol/g. FTIR microscopyshowed bands at 1693 and 3326 cm⁻¹ indicative of the hydroxamatecarbonyl and nitrogen-hydrogen stretches, respectively.

[0263] Step 2: Preparation of Resin III:

[0264] Reaction of Resin II with Nucleophiles

[0265] Resin II (50 mg, 0.046 mmol) was weighed into an 8 mL glass vial,and a 0.5 M solution of a nucleophile in 1-methyl-2-pyrrolidinone (1 mL)was added to the vessel. In the case of phenol and thiophenolnucleophiles, cesium carbonate (148 mg, 0.46 mmol) was added, and in thecase of substituted piperazine nucleophiles, potassium carbonate (64 mg,0.46 mmol) was added. The vial was capped and heated to 70 to 155° C.for 24-48 hr, then cooled to room temperature. The resin was drained andwashed with 1-methyl-2-pyrrolidinone, 1-methyl-2-pyrrolidinone/water(1:1), water, 10% acetic acid/water, methanol, and methylene chloride(3×3 mL each solvent).

[0266] Large Scale Preparation of Resin IIIa:

[0267] Resin II (5 g, 0.91 mmol) was weighed into an oven-driedthree-necked round bottom flask fitted with a temperature probe, anoverhead stirring paddle, and a nitrogen inlet. Anhydrous1-methyl-2-pyrrolidinone (35 mL) was added to the flask followed byethyl isonipecotate (7.0 mL, 45.5 mmol). The resin slurry was stirredslowly with the overhead stirrer, and the mixture was heated to 80° C.with a heating mantle for 65 hr. The flask was thereafter cooled to roomtemperature.

[0268] The resin was collected in a sintered-disk glass funnel andwashed with N,N-dimethylformamide, methanol and methylene chloride (3×30mL each solvent). The resin was dried in vacuo to provide 5.86 g ofresin IIIa as off-white resin beads. The theoretical loading of thepolymer was 0.81 mmol/g. TFA cleavage performed on 50 mg of resin Ea asdescribed in step 3 yielded 10.4 mg of off-white solid spectroscopicallyindistinguishable from a known sample.

[0269] Step 3: Cleavage of Hydroxamic Acids from the Polymer-Support

[0270] Resin III was treated with a trifluoroacetic acid/water mixture(19:1, 1 mL) for 1 hr at room temperature. During that time, the resinbecame a deep red color. The resin was then drained and washed withtrifluoroacetic acid/water (19:1) and methylene chloride (2×1 mL eachsolvent), collecting the combined filtrates in a tared vial. Thevolatiles were removed in vacuo, then a toluene/methylene chloridemixture (2 mL each) was added to the residue. The mixture was againconcentrated in vacuo. The product was characterized by electrospraymass spectroscopy.

[0271] Step 4: Hydrolysis of Polymer-Bound Ester: Preparation of ResinIVa

[0272] Resin IIIa (5.8 g, 4.5 mmol) was weighed into a three-neckedround bottomed flask fitted with an overhead stirring paddle.1,4-Dioxane was added to the flask, and the resin slurry was stirred for15 min. Then, a 4 M solution of KOH (5 mL, 20 mmol) was added, and themixture was stirred for 44 hr. The resin was thereafter collected in asintered-disk glass funnel and washed with dioxane/water (9:1), water,10% acetic acid/water, methanol and methylene chloride (3×30 mL eachsolvent). The resin was dried in vacuo to yield 5.64 g of resin IVa asoff-white polymer beads. FTIR microscopy showed bands at 1732 and 1704cm⁻¹ and a broad band from 2500-3500 cm⁻¹. The theoretical loading ofthe polymer-bound acid was 0.84 mmol/g.

Examples 1-45

[0273] The following compounds were prepared by parallel synthesis(resin based synthesis, automated synthesis) using parallel synthesisfrom Resin IVa as described previously in Preparative Example XI thefollowing compounds were prepared:

MS Example Amine R (M + H) 1 3,5-Dimethylpiperidine

508 2 1-(1-phenylethyl)-piperazine

585 3 1-(2-phenylethyl)-piperazine

585 4 1-(2-chlorophenyl)- piperazine

591 5 1-(4-methoxyphenyl)-2- methylpiperazine

585 6 1-(5-Chloro-2- methylphenyl)piperazine

605 7 1-(2-methoxyphenyl)- piperazine

587 8 1-Acetylpiperazine

523 9 1-(2,4-Dimethylphenyl)- piperazine

585 10 N-(2-hydroxyethyl)- piperazine

525 11 1-(Ethoxy-carbonylmethyl)- piperazine

567 12 1-(2-Fluorophenyl)- piperazine

575 13 1-(2-Furoyl)- piperazine

575 14 1-(Cyclopentyl)-piperazine

549 15 1-(2-Propyl)- piperazine

523 16 N-(2-(1-Piperazino)- acetyl)pyrrolidine

592 17 1-(3-Dimethyl- aminopropyl)- piperazine

566 18 1-(2-Methoxyethyl)- piperazine

539 19 1-(2-Dimethyl-aminoethyl)- piperazine

552 20 1-(2-Ethoxyphenyl)- piperazine

601 21 1-(4-Fluorphenyl)- piperazine

575 22 1-(2-Pyridyl)- piperazine

558 23 2-(1-piperazinyl)-pyrimidine

559 24 4-Piperazino- acetophenone

599 25 1-(4-Nitrophenyl)- piperazine

602 26 1-(3,5-Dichloropyrid-4- yl)piperazine

626 27 4-(2-Methoxyphenyl)- piperidine

586 28 N-[2-Nitro-4- (trifluoromethyl)- phenyl]piperazine

670 29 1-[3-(Trifluormethyl)-pyrid- 2-yl]- piperazine

626 30 cis-3,5-Dimethyl- morpholine

510 31 1-(2,4-Difluorphenyl)- piperazine

593 32 1-(4-Pyridyl)- piperazine

558 33 1-(4-Trifluoromethyl- phenyl)-piperazine

625 34 1-Allylpiperazine

521 35 1-(2-Pyrazinyl)-piperazine

559 36 1-[3-Chloro-5- (trifluoromethyl)pyrid-2- yl)]piperazine

660 37 1-(2-(4-Morpholino)- ethyl)piperazine

594 38 3-Chlorophenyl-piperazine

591 39 4-(Hydroxymethyl)- piperidine

510 40 cis-2,6-Dimethyl-piperazine

509 41 3-Methylpiperidine

494 42 1-[4-(Trifluormethyl)- 2-pyrimidyl]- piperazine

627 43 1-[4-(Trifluormethyl)- 2-pyridyl]- piperazine

626 44 3,5-Dimethyl- piperidine

508 45 3,5-Dimethyl- piperidine

508

Examples 46-47 Step 12: Further Synthesis of Resin III

[0274] Into a 8 mL glass vial was placed resin II (200 mg, 0.18 mmol)and cesium carbonate (0.98 g mg, 3 mmol) (no cesium carbonate used withpiperidine and pyrrolidine nucleophiles). One mL of a 1.8 M solution ofthe amine nucleophile to be reacted in 1-methyl-2-pyrrolidinone (1.8mmol) was added and the vial was capped and heated to 100° C. for 30 hr.Then the vessel was cooled to room temperature, and the resin wasdrained and washed with 1-methyl-2-pyrrolidinone, 1:11-methyl-2-pyrrolidinone/water, water, 1:9 acetic acid/water, methanoland methylene chloride (3×3 mL each solvent).

[0275] The following hydroxamic acids were synthesized from Resin IIIwith the indicated amines, followed by release from the polymer usingthe reaction conditions in Step 3.

Example Amine R MS (M + H) 46 1-(2-Methoxyphenyl)- piperidine

475 47 4-(4-Methoxybenzoyl)- piperidine

503

Example 48 Preparation ofN-hydroxy-4-[[4-(4-methoxyphenoxy)phenyl]sulfonyl]-4-thianecarboxamide

[0276]

[0277] Step 1: Hydrolysis of methyl4-[[4-(4-methoxyphenoxy)phenyl]sulfonyl]-4-thianecarboxylate. To asolution of methyl4-[[4-(4-methoxyphenoxy)-phenyl]sulfonyl]-4-thianecarboxylate (10.0 g,31 mmol) dissolved in tetrahydrofuran (150 mL) was added potassiumtrimethylsilanolate (12.1 g) and stirred 2 hr. Water was added to thereaction mixture and extracted with ethyl acetate (2×100 mL). The pHvalue of the aqueous layer was adjusted to 2 with 2M hydrochloric acidand extracted with ethyl acetate (2×100 mL). The latter organics werewashed with brine, dried over magnesium sulfate, filtered and thesolvent evaporated to afford a pale yellow solid (8.20 g).

[0278] Step 2: Loading on resin. The compound obtained in step 1 (4.0 g,13.1 mmol) was dissolved in 1-methyl-2-pyrrolidinone (15 mL) and addedto a suspension of resin I (6.0 g, 6.6 mmol; Preparative Example XI) in1-methyl-2-pyrrolidinone (40 mL). To this solution were added pyBOP(6.85 g) and N-methylmorpholine (2.9 mL), and the mixture was stirredwith overhead stirring 16 hr. The resin was filtered and washed withdimethylformamide (3×50 mL), methanol (3×50 mL), dichloromethane (3×50mL) and ether (3×50 mL). The resin was dried in vacuo to provide resinMT-III (6.79 g).

[0279] Step 3: Aryl fluoride displacement of resin MT-III. A suspensionof resin MT-III (200 mg, 0.17 mmol), 1-methyl-2-pyrrolidinone (2 mL),cesium carbonate (560 mg) and 4-methoxyphenyl (306 mg) were stirred at105° C. for 16 hr. The reaction mixture was cooled and the resinfiltered. The resin was washed with dimethylformamide (3×5 mL), methanol(3×5 mL), 10% aqueous acetic acid (3×5 mL), methanol (3×5 mL) anddichloromethane (3×5 mL). To the resin was added 95% aqueoustrifluoroacetic acid and the reaction mixture was agitated for 1 hr. Theresin was drained and washed with dichloromethane (2×1 mL). The solventwas evaporated. The residue was purified by RPHPLC to provideN-hydroxy-4-[[4-(4-methoxy-phenoxy)phenyl]sulfonyl]-4-thianecarboxamide(17.9 mg) as a pale yellow oil.

Examples 49-50

[0280] The following hydroxamic acids were prepared by the method ofExample 48 using the appropriate amine.

MS (ES) Example R Amine m/z 49 4-(4-fluoro-benzoyl) 4-(4-fluorobenzoyl)-507 piperidyl piperidine (M + H)⁺ 50 4-(2-methoxy-phenyl)4-(2-methoxyphenyl)- 491 piperidyl piperidine (M + H)⁺

Example 51 Preparation ofN-hydroxy-4-[[4-(4-methoxyphenoxy)phenyl]sulfonyl]-4-thianecarboxamide-1,1-dioxide

[0281]

[0282] Step 1: Oxidation of Resin MT-III. A suspension of resin MT-III(2.0 g, 1.72 mmol), m-chloroperbenzoic acid (4.37 g) and dichloromethane(25 mL) was stirred at room temperature for 20 hr. The resin wasfiltered and washed with dichloromethane (3×25 mL), dimethylformamide(3×25 mL), methanol (3×25 mL), 1M aqueous sodium bicarbonate (2×25 mL),methanol (3×25 mL), dichloromethane (3×25 mL) and ether (3×25 mL). Theresin was dried in vacuo to afford resin MT-IV (2.16 g).

[0283] Step 2: Aryl fluoride displacement of resin MT-IV.N-hydroxy-4-[[4-(4-methoxyphenoxy)-phenyl]sulfonyl]-4-thianecarboxamide1,1-dioxide was prepared by the method of Example 48 using resin MT-IVin the place of resin MT-III. ES (MS) m/z 473 (M+NH₄)⁺.

Example 52

[0284] The following hydroxamic acid was prepared by the method ofExample 51 using 4-(4-fluoro-benzoyl)-piperidine as the amine. MS (ES)m/z 539 (M+H)⁺.

Example 53 Preparation ofN-hydroxy-4-[[4-[4-[(3,5-dimethylpiperidyl)carbonyl]-piperidyl]phenyl]sulfonyl]-4-thianecarboxamide

[0285]

[0286] Step 1: Aryl fluoride displacement of Resin MT-III. To asuspension of resin MT-III (4.06 g, 3.4 mmol) in1-methyl-2-pyrrolidinone (40 mL) was added ethyl isonipecotate (5.25mL), and the mixture was heated to 100° C. for 16 hr. The cooledreaction mixture was filtered and the resin was washed with methanol(3×25 mL), dichloromethane (1×10 mL) and ether (3×25 mL). The resin wasdried in vacuo to afford resin MT-V (4.21 g).

[0287] Step 2: Hydrolysis of resin MT-V. To a suspension of resin MT-V(4.13 g) in tetrahydrofuran (20 mL) was added 4M aqueous potassiumhydroxide (10 mL) and stirred at room temperature for 5 days. The resinwas filtered and washed with methanol (3×25 mL), dichloromethane (3×25mL) and ether (3×25 mL). The resin was dried in vacuo to afford resinMT-VI.

[0288] Step 3: Conversion to amide. To a suspension of resin MT-VI (268mg) in 1-methyl-2-pyrrolidinone (2 mL) were added3,5-dimethyl-piperidine (299 μL), pyBOP (587 mg) and diisopropylethylamine (393 μL), and mixture was stirred 40 hr. The resin was filteredand washed with dimethylformamide (3×2 mL), methanol (3×2 mL), 10%aqueous acetic acid (3×2 mL), methanol (3×2 mL), dichloromethane (3×2mL) and glacial acetic acid (1×2 mL). The resin was treated with 95%aqueous trifluoroacetic acid (2 mL) and agitated 1 hr. The resin waswashed with dichloromethane (2 mL) and methanol (2 mL). The filtrate wasevaporated. The residue was purified by RPHPLC to affordN-hydroxy-4-[[4-[4-[(3,5-dimethylpiperidyl)carbonyl]piperidyl]phenyl]sulfonyl]-4-thianecarboxamide(7.5 mg) MS (ES) m/z 524 (M+H)⁺.

Example 54 Preparation of1,1-dimethylethyl-3,6-dihydro-4-[2-(trifluoromethyl)phenyl]-1(2H)-pyridinecarboxylate

[0289]

[0290] Part A: An oven-dried 1.0 liter flask fitted with a thermometerand nitrogen inlet was charged with 55 mL of a 2 M solution of lithiumdiisopropoylamide in tetrahydrofuran and 50 mL of tetrahydrofuran. Theflask was immersed in a dry ice/acetone bath. When the temperature ofthe solution was less than −70° C., a solution ofN-t-butoxycarbonylpiperidinone (20.0 g, 0.1 mole) in 100 mLtetrahydrofuran was added dropwise, maintaining the temperature lessthan −65° C. After complete addition, the flask was stirred with coolingfor 20 min. Then a solution of N-trifluoromethanesulfonimide (38.2 g,0.107 mole) was added drop-wise maintaining the temperature less than−65° C. After complete addition, the dry ice/acetone bath was swappedwith an ice/water bath. The reaction was stirred overnight (about 18hr), slowly warming to room temperature. After 16 hr, the solvent wasremoved in vacuo, and the residue was purified by column chromatographyon neutral alumina, yielding 26.53 g of product as a yellow oil.Electrospray mass spectroscopy showed m/z 332 (M+H).

[0291] Part B: A three-necked 15 mL round-bottom flask was charged withthe product from Part A (6 g, 18.1 mmol), o-trifluorobenzeneboronic acid(4.94 g, 26 mmol), lithium chloride (2.34 g, 55 mmol), 2 M sodiumcarbonate (26 mL, 52 mmol) and ethylene glycol dimethyl ether (60 mL).Nitrogen was bubbled through the solution for 10 min, then palladiumtetrakistriphenylphosphine (1.06 g, 0.92 mmol) was added. The mixturewas heated to reflux for 1.5 hr, then cooled to room temperature. Thesolvent was removed in vacuo, then the residue was partitioned between100 mL of methylene chloride and 100 mL of 2 M sodium carbonate with 3mL concentrated ammonium hydroxide. The aqueous layer was extracted withan additional 100 mL methylene chloride, then the combined organiclayers were dried over magnesium sulfate and concentrated to give 8.42 gof crude product as a dark brown oil. Purification via flash columnchromatography (10% ethyl acetate3/hexanes) yielded 2.76 g of pureproduct as a yellow oil. Electrospray mass spectroscopy showed m/z 328(M+H).

Example 55 Preparation of1,2,3,6-tetrahydro-4-[2-trifluoromethyl)phenyl]pyridine

[0292]

[0293] The title compound of Example 54 (300 mg, 0.92 mmol) wasdissolved in methylene chloride (5 mL) in a 15 mL round-bottom flask,and 5 mL of trifluoroacetic acid was added dropwise. After 15 min, thesolvent was removed in vacuo, and the residue partitioned between 20 mLof ethyl acetate and 20 mL of 2 M sodium carbonate. The organic layerwas washed with additional 2 M sodium carbonate, dried over magnesiumcarbonate and concentrated in vacuo to yield 195 mg of pure product as acolorless oil. Electrospray mass spectroscopy showed m/z 228 (M+H).

Example 56 Preparation of 4-[2-(trifluoromethyl)phenyl]piperidine

[0294]

[0295] Part A: A solution of the title compound of Example 54 (2.3 g, 7mmol) in 20 mL ethanol was added to a hydrogenation flask containing 1 gof 4% palladium on carbon (0.38 mmol). The mixture was placed under 100PSI hydrogen and heated to 50° C. for 5 hr. Then the mixture was cooledto room temperature and filtered through Celite. The filtrate wasconcentrated in vacuo to give 2.27 g of pure product as a colorless oil.Electrospray mass spectroscopy showed m/z 330 (M+H).

[0296] Part B: The product from Part A above (2.24 g, 6.8 mmol) wasdissolved in 100 mL methylene chloride, and 100 mL of trifluoroaceticacid was added dropwise. After 15 min, the solvent was removed in vacuo,and the residue partitioned between 100 mL of ethyl acetate and 100 mLof 2 M sodium carbonate. The organic layer was washed with additional 2M sodium carbonate, dried over magnesium carbonate and concentrated invacuo to yield 1.12 g of pure product as a colorless oil. Electrospraymass spectroscopy showed m/z 230 (M+H).

Example 57 General Description for Preparation of Hydroxamic Acids viaAryl Fluoride Displacement with Amines

[0297] Part A: A 2 dram vial was charged with aryl fluoro compound ofPreparative Example IV (170 mg, 0.44 mmol), 1 ml of2-methylpyrrolidinone, cesium carbonate (360 mg, 1.1 mmol) and 0.66 mmolof an amine. A small magnetic stirring bar was added, then the vial wascapped and placed in a Pierce Reacti-therm™ at 115° C. The reactionprogress was followed by analytical HPLC. When the reaction was greaterthan 90% complete, the vial was cooled to room temperature. The reactionmixture was diluted with 5 mL of water, then 1.2 mL of 5% hydrogenchloride/water was added dropwise. Then, the entire mixture was pouredonto a column of Celite. The column was washed exhaustively with ethylacetate (30-40 mL) and the filtrate was collected and concentrated togive the crude products.

[0298] Part B: The product from above was dissolved in 2 mL 1,4-dioxaneand 2 mL of methanol in a 4 dram vial with a small magnetic stirringbar. A solution of 4 N hydrogen chloride in 1,4-dioxane was carefullyadded to the reaction, and the mixture was stirred for 2 hr. Then thesolvent was removed in vacuo and the residue purified by preparativereversed-phase HPLC.

Examples 58-60

[0299] The following hydroxamic acids were prepared using the methoddescribed above in Example 57 with the indicated amine as the startingmaterial.

m/z from electrospray mass Example amine R spectroscopy 58 Product ofExample 56

513.3 (M + H) 59 Product of Example 55

511.2 (M + H) 60 4-(2-keto- benzimid- azolinyl)- piperidine

501 (M + H)

Examples 61-69

[0300] Using the procedures outlined in Examples 54, 55, and 57 andother methods outlined above, the following analogs are made from theindicated boronic acid:

Example Boronic acid R 61

62

63

64

65

66

67

68

69

Example 70 Preparation of4-[[4-[4-[(3,5-dimethyl-1-piperidinyl)carbonyl]-1-piperidinyl]-phenyl]sulfonyl]-N-hydroxy-1-(2-methoxyethyl)-4-piperidinecarboxamide,monohydrochloride

[0301]

[0302] Part A: To a solution of isonipecotic acid (5.8 g, 44.9 mmol) inwater (200 mL) was added sodium carbonate (4.62 g, 44.9 mmol) followedby the drop-wise addition of di-tert-butyl-dicarbonate (10.1 g, 46.3mmol) in dioxane (40 mL). After 4 hr, the solvent was concentrated invacuo and the solution was extracted with ethyl ether. The aqueous layerwas acidified with 3N hydrochloric acid to pH=2. The solution wasextracted with ethyl ether and the organic layer was washed withsaturated aqueous sodium chloride and dried over magnesium sulfate.Concentration in vacuo provided N-Boc-isonipecotic acid as a white solid(9.34 g, 90%).

[0303] Part B: To a solution of the N-Boc-isonipecotic acid of part A(1.0 g, 4.37 mmol) in dichloromethane (10 mL) was added1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (853 mg,4.45 mmol), 1-hydroxybenzotriazole hydrate (620 mg, 4.59 mmol)3,5-dimethylpiperdine (0.67 mL, 5.03 mmol) and diisopropylethylamine(1.67 mL, 9.61 mmol) and was stirred for 21 hr. The solution wasconcentrated in vacuo. The residue was diluted with ethyl acetate andwashed with 1M hydrochloric acid, saturated sodium bicarbonate andsaturated aqueous sodium chloride and dried over sodium sulfate.Concentration in vacuo provided the amide as a clear colorless oil (1.21g, 89%).

[0304] Part C: To a solution of the amide of part B (1.20 g, 3.84 mmol)in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL) and thesolution was stirred for 1 hr. Concentration in vacuo provided an oilwhich was added directly to a solution of the compound of PreparativeExample VII, Part A (956 mg, 2.56 mmol) in dimethylacetamide (10 mL).Cesium carbonate (2.92 g, 8.96 mmol) was added and the solution washeated to 100° C. for 18 hr. The solution was partitioned between ethylacetate and water and the organic layer was washed with water andsaturated sodium chloride and dried over sodium sulfate. Concentrationin vacuo provided the phenylamine as an oil (1.53 g, 68%). MS(CI) MH⁺calculated for C₃₀H₄₇N₃O₆S: 578, found 578.

[0305] Part D: To a solution of the phenylamine of part C (1.5 g, 2.6mmol) in ethanol (9 mL) and tetrahydrofuran (9 mL) was added sodiumhydroxide (1.02 g, 26 mmol) in water (5 mL) and the solution was heatedto 60° C. for 20 hr. The solution was concentrated and the residue wasdiluted with water and acidified to pH=3 with 3N hydrochloric acid.Vacuum filtration provided the acid as a beige solid (500 mg, 33%).MS(CI) MH⁺ calculated for C₂₈H₄₃N₃O₆S: 550, found 550.

[0306] Part E: To a solution of the acid of part D (492 mg, 0.84 mmol)in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazolehydrate (136 mg, 1.01 mmol), 4-methylmorpholine (0.46 mL, 4.20 mmol),and O-tetrahydropyranyl hydroxylamine (147 mg, 1.26 mmol). After 1 hr,1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (225 mg,1.18 mmol) was added and the solution was stirred for 72 hr at ambienttemperature. The solution was partitioned between ethyl acetate andwater. The organic layer was washed with water and saturated sodiumchloride and dried over sodium sulfate. Concentration in vacuo providedthe protected hydroxamate as an oil (524 mg, 96%). MS(CI) MH⁺ calculatedfor C₃₃H₅₁N₄O₇S: 649, found 649.

[0307] Part F: To a solution of the protected hydroxamate of part E (514mg, 0.79 mmol) in 1,4-dioxane (10 mL) was added 4M hydrochloric acid indioxane (10 mL) and the solution was stirred for 1.5 hr. The solutionwas concentrated in vacuo and trituration (ethyl ether) provided thetitle compound as a white solid (360 mg, 76%). MS(CI) MH⁺ calculated forC₂₈H₄₄N₄O₆S: 565, found 565. HRMS calculated for C₂₈H₄₄N₄O₆S: 565.3060,found 565.3070. Analytical calculation for C₂₈H₄₄N₄O₆S 2HCl:2H₂O: C,49.92; H, 7.48; N, 8.32; S, 4.76; Cl, 10.52. Found: C, 49.41; H, 7.55;N, 7.85; S, 4.53; Cl, 10.78.

Example 71 Preparation of4-[[4-[4-[(3,5-dimethyl-1-piperidinyl)carbonyl]-1-piperidinyl]-phenyl]sulfonyl]-N-hydroxy-1-(2-methoxyethyl)-4-piperidinecarboxamide

[0308]

[0309] A solution of the hydroxamate of Example 70, part F (50 mg, 0.08mmol) in water (2 mL) was neutralized with saturated sodium bicarbonate.The aqueous solution was extracted with ethyl acetate. Concentration invacuo provided the hydroxamate free base as an orange solid (35 mg,75%).

Example 72 Preparation ofrel-4-[[4-[4-[[(3R,5R)-3,5-dimethyl-1-piperidinyl]carbonyl]-1-piperidinyl]phenyl]sulfonyl]-N-hydroxy-4-piperidinecarboxamide,monohydrochloride

[0310]

[0311] Part A: To a solution of the N-Boc-isonipecotic acid of Example70, Part A (1.0 g, 4.37 mmol) in dichloromethane (10 mL) was added1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (853 mg,4.45 mmol), 1-hydroxybenzotriazole hydrate (620 mg, 4.59 mmol)3,5-dimethylpiperdine (0.67 mL, 5.03 mmol) and diisopropylethylamine(1.67 mL, 9.61 mmol) and was stirred for 21 hr. The solution wasconcentrated in vacuo. The residue was diluted with ethyl acetate andwashed with 1M hydrochloric acid, saturated sodium bicarbonate andsaturated sodium chloride and dried over sodium sulfate. Concentrationin vacuo provided the amide as a clear colorless oil (1.4 g,quantitative yield).

[0312] Part B: To a solution of the amide of part A (1.4 g, 4.49 mmol)in dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) andthe solution was stirred for 1 hr. Concentration in vacuo provided asolid that was added directly to a solution of the compound ofPreparative Example II, Part D, (1.24 mg, 2.99 mmol) indimethylacetamide (10 mL). Cesium carbonate (3.42 g, 10.5 mmol) wasadded and the solution was heated to 100° C. for 20 hr. The solution waspartitioned between ethyl acetate and water and the organic layer waswashed with water and saturated sodium chloride and dried over sodiumsulfate. Concentration in vacuo provided the phenylamine as a yellowsolid (1.90 g, quantitative yield). MS(CI) MH⁺ calculated forC₃₂H₄₉N₃O₇S: 620, found 620.

[0313] Part C: To a solution of the phenylamine of part B (1.9 g, 3.0mmol) in ethanol (10 mL) and tetrahydrofuran (10 mL) was added sodiumhydroxide (1.2 g, 30 mmol) in water (5 mL) and the solution was heatedto 60° C. for 20 hr. The solution was concentrated and the residue wasdiluted with water and acidified to pH=1 with 3N hydrochloric acid. Thesolution was extracted with ethyl acetate and washed with 1Mhydrochloric acid and saturated sodium chloride and dried over magnesiumsulfate. Concentration in vacuo provided the acid as a yellow oil (1.9g, quantitative yield). MS(CI) MH⁺ calculated for C₃₀H₄₅N₃O₇S: 592,found 592.

[0314] Part D: To a solution of the acid of part C (1.87 g, 3.00 mmol)in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazolehydrate (486 mg, 3.6 mmol), 4-methylmorpholine (1.65 mL, 15 mmol), andO-tetrahydropyranyl hydroxylamine (526 mg, 4.5 mmol). After 1 hr,1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (805 mg,4.2 mmol) was added and the solution was stirred for 18 hr at ambienttemperature. The solution was partitioned between ethyl acetate andwater. The organic layer was washed with water and saturated sodiumchloride and dried over sodium sulfate. Chromatography (on silica, ethylacetate/hexane) provided the protected hydroxamate as an oil (1.63 g,79%).

[0315] Part E: To a solution of the protected hydroxamate of part D(1.61 g, 2.33 mmol) in dioxane (10 mL) was added 4M hydrochloric acid indioxane (10 mL) and the solution was stirred for 45 min. The solutionwas concentrated in vacuo and trituration (ethyl ether) a white solid.Reverse phase chromatography (on silica, acetonitrile/water(hydrochloric acid)) produced fractions A, B, C and D. Concentration invacuo of fraction A provided the title compound as a white solid (59mg). MS(CI) MH⁺ calculated for C₂₅H₃₈N₄O₅S: 507, found 507.

Example 73 Preparation of rel-1,1-dimethylethyl4-[[4-[4-[[(3R,5R)-3,5-dimethyl-1-piperidinyl]carbonyl]-1-piperidinyl]-phenyl]sulfonyl]-4-[(hydroxyamino)-carbonyl]-1-piperidinecarboxylate

[0316]

[0317] From the reverse phase chromatography of Example 72, Part E,fraction C was concentrated in vacuo to provide the title compound as awhite solid (49 mg). MS(CI) MH⁺ calculated for C₃₀H₄₆N₄O₇S: 607, found607.

Example 74 Preparation ofrel-4-[[4-[4-[[(3R,5S)-3,5-dimethyl-1-piperidinyl]carbonyl]-1-piperidinyl]phenyl]sulfonyl]-N-hydroxy-4-piperidinecarboxamide,monohydrochloride

[0318]

[0319] From the reverse phase chromatography of Example 72, Part E,fraction B was concentrated in vacuo to provide the title compound as awhite solid (198 mg). MS(CI) MH⁺ calculated for C₂₅H₃₈N₄O₅S: 507, found507.

Example 75 Preparation of rel-1,1-dimethylethyl4-[[4-[4-[[(3R,5S)-3,5-dimethyl-1-piperidinyl]carbonyl]-1-piperidinyl]-phenyl]sulfonyl]-4-[(hydroxyamino)-carbonyl]-1-piperidinecarboxylate

[0320]

[0321] From the reverse phase chromatography of Example 72, Part E,fraction D was concentrated in vacuo to provide the title compound as awhite solid (242 mg). MS(CI) MH⁺ calculated for C₃₀H₄₆N₄O₇S: 607, found607.

Example 76 Preparation of4-[[4-[4-[(2,3-dihydro-1H-indol-1-yl)carbonyl]-1-piperidinyl]-phenyl]sulfonyl]-N-hydroxy-1-(2-methoxyethyl)-4-piperidinecarboxamide,monohydrate

[0322]

[0323] Part A: To a solution of the N-Boc-isonipecotic acid ofPreparative Example I, Part B (750 mg, 3.27 mmol) in dichloromethane (3mL) was added 2-chloro-4,6-dimethoxy-1,3,5-triazine (564 mg, 3.21 mmol).The solution was cooled to 0° C. and 4-methylmorpholine (0.35 mL, 3.21mmol) was added. After 2 hr, indoline (0.36 mL, 3.21 mmol) was added andthe solution was stirred for 22 hr at ambient temperature. The solutionwas concentrated in vacuo. The residue was diluted with ethyl acetateand washed with 1M hydrochloric acid, saturated sodium bicarbonate andsaturated sodium chloride and dried over sodium sulfate. Concentrationin vacuo provided the amide as a pink solid (940 mg, 89%).

[0324] Part B: To a solution of the amide of part A (935 g, 2.83 mmol)in 1,4-dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL)and the solution was stirred for 1 hr. Concentration in vacuo providedan oil which was added directly to a solution of the compound ofPreparative Example VII, Part A, (705 mg, 1.89 mmol) indimethylacetamide (10 mL). Cesium carbonate (2.15 g, 6.61 mmol) wasadded and the solution was heated to 110° C. for 18 hr. The solution waspartitioned between ethyl acetate and water and the organic layer waswashed with water and saturated sodium chloride and dried over sodiumsulfate. Concentration in vacuo provided the phenylamine as an orangeoil (893 mg, 81%). MS(CI) MH⁺ calculated for C₃₁H₄₁N₃O₆S: 584, found584.

[0325] Part C: To a solution of the phenylamine of part B (885 g, 1.52mmol) in ethanol (10 mL) and tetrahydrofuran (10 mL) was added sodiumhydroxide (607 mg, 15.2 mmol) in water (5 mL) and the solution washeated to 60° C. for 20 hr. The solution was concentrated and theresidue was diluted with water and acidified to pH=1 with 3Nhydrochloric acid producing a solid. Vacuum filtration provided the acidas a beige solid (475 g, 53%). MS(CI) MH⁺ calculated for C₂₉H₃₇N₃O₆S:556, found 556.

[0326] Part D: To a solution of the acid of part C (465 g, 0.79 mmol) inN,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate(128 mg, 0.95 mmol), 4-methylmorpholine (0.43 mL, 3.95 mmol), andO-tetrahydropyranyl hydroxylamine (139 mg, 1.18 mmol). After 1 hr,1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (212 mg,1.10 mmol) was added and the solution was stirred for 18 hr at ambienttemperature. The solution was partitioned between ethyl acetate andwater. The organic layer was washed with water and saturated sodiumchloride and dried over sodium sulfate. Chromatography (on silica, ethylacetate/methanol) provided the protected hydroxamate as a yellow oil(305 mg, 60%). MS(CI) MH⁺ calculated for C₃₄H₄₆N₄O₇S: 655, found 655.

[0327] Part E: To a solution of the protected hydroxamate of part D (300mg, 0.46 mmol) in dioxane (5 mL) was added 4M hydrochloric acid indioxane (5 mL) and the solution was stirred for 2 hr. The resultingsolid was collected by vacuum filtration. Washing with ethyl etherprovided the title compound as a white solid (260 mg, 94%). MS(CD) MH⁺calculated for C₂₉H₃₄N₄O₆S: 571, found 571.

[0328] The following compounds were prepared by parallel synthesis(resin based synthesis, automated synthesis) procedures utilizingreactions such as acylation and nucleophilic displacement:

Example 77

[0329]

Example 78

[0330]

Example 79

[0331]

Examples: 80-118

[0332]

Example R₁R₂NH Amine MS (ES) m/z 80

Ethyl amine 592 (M + H) 81

3-(Aminomethyl) pyridine 655 (M + H) 82

Imidazole 615 (M + H) 83

3-Amino-1-propanol 622 (M + H) 84

Histamine 658 (M + H) 85

2-Thiophene methyl amine 660 (M + H) 86

Morpholine 634 (M + H) 87

2-(Aminomethyl) pyridine 655 (M + H) 88

4-(Aminomethyl) pyridine 655 (M + H) 89

Ethanolamine 608 (M + H) 90

N,N,N-Trimethyl ethylenediamine 649 (M + H) 91

1-Methylpiperazine 647 (M + H) 92

N,N-Dimethyl ethylenediamine 635 (M + H) 93

Piperazine 633 (M + H) 94

Thiomorpholine 650 (M + H) 95

N-Propylcyclopropne methylamine 660 (M + H) 96

(Aminomethyl) cyclopropane 618 (M + H) 97

Dimethylamine 592 (M + H) 98

Diethylamine 620 (M + H) 99

Piperidine 632 (M + H) 100

(R)-(-)-2-Pyrrolidine methanol 648 (M + H) 101

Pyrrolidine 618 (M + H) 102

1-(2-(2-Hydroxyethoxy) ethyl)piperazine 721 (M + H) 103

Isonipecotamide 675 (M + H) 104

2-(2-Aminoethoxy) ethanol 652 (M + H) 105

3,3′-Iminobis(N,N- dimethylpropylamine) 734 (M + H) 106

Bis(2-Methoxy ethyl)amine 680 (M + H) 107

4-Hydroxy piperidine 648 (M + H) 108

N-(Carboethoxy methylpiperazine 719 (M + H) 109

1-(2-Morpholinoethyl) piperazine 746 (M + H) 110

1-(2-Methoxyethyl) piperazine 691 (M + H) 111

1-(2- Dimethylaminoethyl) piperazine 704 (M + H) 112

2-Methoxyethylamine 622 (M + H) 113

2,2,2-Trifluoroethyl amine 646 (M + H) 114

1,2,4-Triazole 616 (M + H) 115

Methoxyamine 594 (M + H) 116

Ethyl isonipecotate 704 (M + H) 117

2-Pyrrolidinone 632 (M + H) 118

Isonipecotic acid 676 (M + H)

Example 119 Preparation of

[0333]

[0334] Part A. Preparation of aryl fluoride. To a solution of ethyl4-[(4-fluorophenyl)sulfonyl]-1-(2-methoxyethyl)-4-piperidinecarboxylate(57 mmol) in dioxane (90 mL) and water (45 mL) was added LiOH (4.8 g,3.5 eq). The mixture was stirred at 60° C. overnight, cooled to roomtemperature, and concentrated in vacuo. The aqueous layer was treatedwith concentrated HCl until the pH was approximately 4. The solid wascollected and dried. Next, the solid (47.8 mmol) in DMF (100 mL) wasadded NMM (26.2 mL, 239 mmol) and(benzotriazol-1-yl)-N,N,N′,N′-bis(tetramethylene)uroniumtetrafluoroborate (32.3 g, 62.1 mmol). The mixture was stirred at roomtemperature for 15 min, and O-(tetrahydro-211-pyran-2-yl)hydroxylamine(6.71 g, 57.32 mmol) was then added. After 48 hr at room temperature,the mixture was quenched with sat. NH₄ ⁺Cl⁻, and then extracted withCH₂Cl₂ three times. The combined organic layer was dried andconcentrated in vacuo. The residue was purified over SiO₂ usinghexane/CH₂Cl₂ and then CH₂Cl₂/MeOH to give 20 g of protectedhydroxyamide as an orange oil.

[0335] Part B. Aryl fluoride displacement. A solution of the arylfluoride from Part A (0.45 mmol), Cs₂CO₃ (1.35 mmol, 3 eq), and4-(4-chlorobenzoyle)piperidine (Maybridge Chemical Co., England, 0.67mmol, 1.5 eq) in DMSO (1 mL) was heated to 110° C. for 18-48 hr. Themixture was then cooled, dissolved in saturated aq. NH₄ ⁺Cl⁻ (5 mL), andextracted with dichloromethane (3×3 mL). The combined organic layer wasblown down. The crude product was purified by RPHPLC (eluting with 10%to 90% acetonitrile/water), and the pure fractions were combined andconcentrated.

[0336] Part C. Conversion of the THP hydroxamic acid of Part B to thehydroxamic acid. The residue from Part B was dissolved in 2 mL of 4M HCland 1 mL of MeOH, stirred at room temperature for 1 h, and then blowndown. THEO M+H=564.1935; Observed: HI RES M+H=564.1949.

Example 120 Preparation of

[0337]

[0338] Part A. Preparation of 4-(4-n-propylbenzoyl)piperidine. To asolution of magnesium (147 mmol, 5 eq) in 40 mL of THF at 0° C. wasadded 1-bromo-4-(n-propyl)benzene (88.24 mmol, 3 eq). The solution wasallowed to warm to room temperature over approximately 3 hr. The weinrebamide (29.4 mmol, 1 eq) having the following structure:

[0339] was added, and then the mixture was stirred at room temperaturefor 18 hr. The mixture was quenched with saturated NH₄ ⁺Cl⁻, and thenextracted with CH₂Cl₂ three times. The combined organic layer was washedwith saturated NH₄ ⁺Cl⁻, dried over MgSO₄, and concentrated in vacuo.The residue was purified over 70 g of SiO₂, eluting withethylacetate:hexanes (1:10) to ethylacetate:hexanes (1:3). Thepiperidine was dissolved in 20 mL of CH₂Cl₂ and 20 mL oftrifluoroacetate. The resulting mixture was stirred at room temperaturefor 1 hr, and then concentrated in vacuo. The residue was treated with5% NaOH until a solid precipitated out. The solid was collected and thendissolved in dichloromethane, dried, and concentrated in vacuo. Theresidue was recrystallized in MeOH/Ether to give 5.07 g of4-(4-n-propylbenzoyl)piperidine.

[0340] Part B. Aryl fluoride displacement. A solution of the arylfluoride (0.45 mmol., as prepared in Part A of the preceding example),Cs₂CO₃ (1.35 mmol, 3 eq), and the 4-(4-n-propylbenzoyl)piperidineprepared in Part A above (0.65 mmol, 1.5 eq) in DMSO (1 mL) was heatedto 110° C. for 18-48 hr. The mixture was cooled, dissolved in saturatedaqueous NH₄ ⁺Cl⁻ (5 mL), and extracted with dichloromethane (3×3 mL).The combined organic layer was blown down. The crude product waspurified by RPHPLC (eluting with 10% to 90% acetonitrile/water), and thepure fractions were combined and concentrated.

[0341] Part C. Conversion of the THP hydroxamic acid of Part B to thehydroxamic acid. The residue from Part C was dissolved in 2 mL of 4M HCland 1 mL of MeOH, stirred at room temperature for 1 h, and then blowndown. Theo: M+H=572.2794; Observed: Hi Res M+H=572.2755;

Example 121 Preparation of

[0342]

[0343] Part A:

[0344] To a solution of n-butylthiophene (Lancaster, 5.0 g, MW 140.26,1.1 eq) in tetrahydrofuran (80 ml) at 0° C. was dripped in 1.6 Mn-butyllithium in hexanes (Aldrich, 24 ml, 1.2 eq). The mixture stirredat 0° C. for 0.5 hr under N₂. The reaction vessel was then cooled to−78° C., and a solution of the weinreb amide (shown in the reactionabove) in tetrahydrofuran (30 ml) was slowly added. The dry ice bath wasremoved, and the reaction was allowed to warm to room temperature. After3 hr, the conversion was complete. The reaction was quenched with water(50 ml), and the organic layer was removed in vacuo. More water (100 ml)was added, and the mixture was extracted with diethylether (3×100 ml).The organic layers were washed with water (2×) and brine (1×), driedover Na₂SO₄, and concentrated to afford a brown oil that waschromatographed (ethylacetate:hexanes, 1:9) to afford 7.5 g of a paleyellow solid (67% crude yield). ¹H NMR showed the desired compound.

[0345] Part B:

[0346] To a solution of Compound I (7.4 g, MW 351.50, 1.0 eq) inacetonitrile (10 ml) was added 4 N HCl in dioxane (Pierce, 40 ml). After1 hr, the solvent was evaporated, and the residue was slurried indiethylether to afford a white solid that was collected and dried for5.8 g (97% yield). ¹H NMR showed the desired Compound II.

[0347] Part C:

[0348] To a solution of Compound II (2.1 g, MW 287.85, 1.5 eq) indimethylsulfoxide (Aldrich, 15 ml) was added CsCO₃ (Aldrich, 6.4 g, MW325.8, 4.0 eq). After stirring for 5 min, Compound III (2.0 g, MW401.49, 1.0 eq) was added, and the mixture was stirred at 90° C. for 24hr. The mixture was then diluted with water (15 ml), and extracted withethylacetate (3×100 ml). The organic layer was washed with water (1×),washed with brine (2×), dried over Na₂SO₄, and concentrated to a crudebrown solid which was recrystallized from hot methanol for 1.83 g of anorange crystalline solid (59% yield). ¹H NMR showed the desired CompoundIV.

[0349] Part D:

[0350] To a solution of Compound IV (1.8 g, MW 632.88, 1.0 eq) inmethylene chloride (5 ml) was added trifluoroacetic acid (10 ml). Themixture was stirred for 4 hr at room temperature. The mixture was thenconcentrated to ⅓ volume, and diethylether was added to afford a solid,which was collected and dried for 1.4 g tan solid (88% yield). ¹H NMRand LCMS showed the desired Compound V.

[0351] Part E:

[0352] To a solution of Compound V (1.3 g, 2.2 mmol) inN,N-dimethylformamide (8 ml) was added triethylamine (Aldrich, 1.2 ml,8.8 mmol), followed by N-hydroxybenzotriazole hydrate (Aldrich, 0.6 g,4.4 mmol), O-tetrahydro-2H-pyran-2-yl)hydroxylamine (0.4 g, 3.3 mmol),and, lastly, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(Sigma, 0.9 g, 4.8 mmol). The mixture was stirred for 2 days at roomtemperature. The mixture was diluted with water (10 ml), and extractedwith ethylacetate (3×75 ml). The organic layers were combined, andwashed with a saturated sodium bicarbonate solution (1×1 50 ml) andbrine (1×150 ml). The organic layer was then dried over Na₂SO₄, andconcentrated to afford an orange foam that was recrystallized frommethanol to afford a pale yellow solid (1.2 g, 80% yield). ¹H NMR andLCMS showed the desired Compound VI.

[0353] Part F:

[0354] The Compound VI (1.2 g, 1.8 mmol) was treated with methanol (0.5ml) and 4 N HCl in dioxane (5 ml) for 1 hr. The solvents wereconcentrated to ⅓ the volume via an N₂ stream. Diethylether was thenadded to the residue to afford a solid that was collected and dried to awhite solid (1.0 g, 91% yield). ¹H NMR showed the desired Compound VII.HRMS confirmed this finding (theo M=H 592.2515, observed: 592.2498).

Example 122 Preparation of

[0355]

[0356] Part A:

[0357] To an ice-cold suspension of isopropylphosphonium iodide(Aldrich, 40.7, MW 432.29, 3.0 eq) at 0° C. in tetrahydrofuran (240 ml)was slowly added n-butyllithium (Aldrich, 1.6 M, 58.9 ml, 3.0 eq). After1 hr, a solution of 5-bromo-2-thiophene carboxaldehyde (Aldrich, 6.0 g,MW 191.05, 1.0 eq) in tetrahydrofuran (60 ml) was added in one shot. Theice bath was removed, and the mixture warmed to ambient temperature andstirred 2.5 hours. The reaction was quenched with water (110 ml)followed by 1 N HCl (110 ml). An emulsion developed that was filteredthrough a coarse frit funnel. The filtrate was separated and the organicwas washed with brine (200 ml), dried over Na₂SO₄, and concentrated toafford a black oil. Purification on silica gel (ethyl acetate/hexanes)gave 3.4 g of a yellow oil (50% yield). ¹H NMR showed desired CompoundI.

[0358] Part B:

[0359] To a solution of Compound I (2.89 g, MW 217.13, 1.5 eq) intetrahydrofuran (25 ml) at −40° C. was dripped 2.0M isopropylmagnesiumchloride in tetrahydrofuran (Aldrich, 6.9 ml, 1.55 eq). The mixture wasstirred at −40° C. for 1.5 hr under N₂. A solution of the weinreb amide(shown in the above reaction) in tetrahydrofuran (30 ml) was quicklyadded. The dry ice bath was removed, and the mixture was allowed to warnto room temperature and stirred overnight. The reaction was quenchedwith 1 N HCl (25 ml), followed by water (25 ml). The organic layer wasremoved in vacuo. The aqueous residue was extracted with diethylether(3×100 ml). The organic layers were washed with water (2×) and brine(1×), dried over Na₂SO₄, and concentrated to afford a brown oil that wasslurried with hexanes. A solid formed, which was subsequently filteredto afford 1.9 g of gray solid (61% crude yield). ¹H NMR showed thedesired Compound II.

[0360] Part C:

[0361] To Compound II (1.9 g, MW 349.49, 1.0 eq) was added 4 N HCl indioxane (Pierce, 10 ml). After 1 hr, the solvent was evaporated, and theresidue was slurried in diethylether to afford a gray solid that wascollected and dried for 1.4 g (93% yield). ¹H NMR showed the desiredCompound III.

[0362] Part D:

[0363] To a solution of Compound III (1.4 g, MW 285.83, 1.5 eq) indimethylsulfoxide (Aldrich, 10 ml) was addded CsCO₃ (Aldrich, 4.0 g, MW325.8, 4.0 eq). After 5 min, Compound IV (1.3 g, MW 401.49, 1.0 eq) wasadded, and the reaction was stirred at 100° C. for 24 hr. The mixturewas then diluted with water (15 ml), and extracted with ethylacetate(3×100 ml). The organic layers were washed with water (1×) and brine(2×), dried over Na₂SO₄, and concentrated for a crude yellow solid,which was recrystallized from hot methanol for 0.98 g of a yellowcrystalline solid (50% yield). LCMS (M+H) showed the desired Compound V.

[0364] Part E:

[0365] To a solution of Compound V (0.98 g, MW 630.86, 1.0 eq) inmethylene chloride (4 ml) was added trifluoroacetic acid (4 ml, TFA).The mixture was stirred for 4 hr at room temperature. The mixture wasthen concentrated to ⅓ volume, and diethylether was added to afford asolid, which was collected and dried for 1.0 g tan solid (93% yield). ¹HNMR and LCMS showed the desired Compound VI.

[0366] Part F:

[0367] To a solution of Compound VI (1.0 g, MW 688.77, 1.0 eq) inN,N-dimethylformamide (5 ml) was added triethylamine (Aldrich, 0.8 ml,MW 101.19, 4.0 eq) followed by N-hydroxybenzotriazole hydrate (Aldrich,0.38 g, MW 135.13, 2.0 eq),)-(tetrahydro-2H-pyran-2-yl), hydroxylamine(0.25 g, MW 117.16, 1.5 eq), and, lastly,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (Sigma, 0.59g, MW 191.76, 2.2 eq). The mixture stirred at ambient temperature for 18hr. To work up the reaction was diluted with water (10 ml) and extractedwith ethylacetate (3×75 ml). The organics were combined and washed witha saturated sodium bicarbonate solution (1×150 ml), and brine (1×150ml). The organic was then dried over Na₂SO₄, and concentrated to afforda 0.9 g of a brown oil (96% yield). ¹H NMR and LCMS showed the desiredCompound VII.

[0368] Part G:

[0369] The Compound VII (0.9 g, MW 673.88, 1.0 eq) was treated withmethanol (0.5 ml) and 4 N HCl in dioxane (5 ml) for 1 hr). The solventswere concentrated to ⅓ the volume via an N₂ stream. Diethylether wasthen added to the residue to afford a solid that was collected and driedfor a brown solid (0.32 g, 40% yield). ¹H NMR showed the desiredCompound VIII. HRMS confirmed this observation (theo. M+H 590.2359,observed M+H 590.2364).

Example 123 Preparation of

[0370]

[0371] Part A. Preparation of Aryl Fluoride Ester:

[0372] To a solution of molecular slieves (7.5 g), ethyl5-[(4-fluorophenyl(sulfonyl]-4-piperidinecarboxylate, monohydrate (15 g,42.6 mmol) in methanol (75 mL), and acetic acid (9 mL) was added sodiumcyano borohydride (7.23 g, 115 mmol). The mixture was stirred at roomtemperature for 48 hr. The mixture was then quenched with sat. NH₄ ⁺Cl⁻,and extracted with CH₂Cl₂ three times. The combined organic layer wasdried and concentrated in vacuo. The residue was then recrystallizedusing ethanol and ether to give 12.1 g (32.7 mmol) of the aryl fluorideester.

[0373] Part B. Aryl fluoride displacement. A solution of the arylfluoride from Part A (0.45 mmol), Cs₂CO₃ (1.35 mmol, 3 eq), and4-(4-chlorobenzoyle)piperidine (Maybridge, England, 0.67 mmol, 1.5 eq)in DMSO (1 mL) was heated to 1110° C. for 18-48 h. The mixture wascooled, dissolved in saturated aqueous NH₄ ⁺Cl⁻ (5 mL), and extractedwith dichloromethane (3×3 mL). The combined organic layer was blowndown, and the crude product was purified by crystallization usingethanol and ether.

[0374] Part C. Converting the ethyl ester to the hydroxamic acid. Asolution of ethyl ester (5 g) in ethanol (8 mL), tetrahydrofuran (4 mL),and 50% aqueous NaOH (2 mL) was heated to 50° C. for approximately 2 hr(additional ethanol and THF can be added if the solid was not completelysoluble after 1 hr at 50° C.). The residue was neutralized to a pH of5-6 with aqueous HCl. The aqueous layer was concentrated in vacuo, andthe resulting solid was washed with acetonitrile and water, and driedunder high vacuum. A solution of the acid, NMM (3 eq), EDC (1.4 eq), andHOBT (1.5 eq) in DMF (5 mL) was heated at 40° C. for 2 hr. The amine wasadded, and then stirred at room temperature for 18-48 hr. The reactionmixture was quenched with saturated aqueous NH₄ ⁺Cl⁻, and extracted withdichloromethane. The combined organic layer was concentrated. The THPamide was purified over SiO₂ using CH₂Cl₂/methanol/triethylamine (theTHP amide may alternatively be purified by reverse-phasechromatography). The resulting solid was then dissolved in 10 mL of 4MHCl and 10 mL of methanol, and stirred at room temperature untilcompletion (30 min to 120 min). The mixture was then blown down, and theresulting solid was re-dissolved in methanol and poured into isopropylalcohol. The solid was collected and dried. THEO M+H=560.1986; observedHI RES M+H=560.1999.

Example 124 Preparation of

[0375]

[0376] Part A. Preparation of 4-(4-metholcyclopropylbenzoyl)piperidine.To a solution of 4-bromophenylcyclopropyl ketone (Acros, 20 g, 89 mmol)in THF (75 mL) was added sodium borohydride (2.25 g, 60 mmol) andaluminum trichloride (3.95 g, 30 mmol) in small portions at −5° C. Themixture was allowed to warm to room temperature for 18 hr, and thenstirred an additional 3 hr at 40° C. The mixture was then cooled,quenched with saturated NH₄ ⁺Cl⁻, and extracted with CH₂Cl₂ three times.The combined organic layer was dried and concentrated in vacuo. Themixture was chromatographed over 70 g of SiO₂ eluting with EtOAc:Hexane(0:100 to 10:90) to give 14.55 g (69 mmol) of 4-methyl cyclopropyl arylbromide. To a cooled to 0° C. solution of the 4-methyl cyclopropyl arylbromide (7.75 g, 36.7 mmol) in 20 mL of THF was added magnesium (55mmol, 3 eq), followed by dibromoethane (10 uL) in small portions,keeping the mixture cold. The solution was stirred for 3 hr. The weinrebamide described in Example 120 (5 g, 18.4 mmol) was added at 0° C., andthe mixture was stirred at room temperature for 48 hr. The mixture wasthen quenched with saturated NH₄ ⁺Cl⁻, and extracted with CH₂Cl₂ threetimes. The combined organic layer was dried and concentrated in vacuo.The mixture was chromatographed over 70 g of SiO₂ eluting withEtOAc/Hexane (0:100 to 30:70) to give 5.54 g (16 mmol) of the desiredBOC-protected piperidine. The BOC-protected piperidine was thendissolved in 20 mL of CH₂Cl₂ and 20 mL of TFA, and stirred at roomtemperature for 1 hr. The mixture was concentrated in vacuo, and theresidue was treated with 5% NaOH and water, and then extracted withCH₂Cl₂ three times. The combined organic layer was dried andconcentrated in vacuo to give 3.47 g (14.3 mmol) of the4-(4-metholcyclopropylbenzoyl)piperidine.

[0377] Part B. Aryl fluoride displacement. A solution of ethyl4-[(4-fluorophenyl)sulfonyl]-1-(2-methoxyethyl)-4-piperidinecarboxylate(0.45 mmol), Cs₂CO₃ (1.35 mmol, 3 eq), and4-(4-metholcyclopropylbenzoyl)piperidine from Part A in DMSO (1 mL) washeated to 110° C. for 18-48 h. The mixture was cooled, dissolved insaturated aqueous NH₄ ⁺Cl⁻ (5 mL), and extracted with dichloromethane(3×3 mL). The combined organic layer was blown down, and the crudeproduct was purified by crystallization using ethanol and ether.

[0378] Part C. Converting the ethyl ester to the hydroxamic acid. Asolution of ethyl ester (5 g) in ethanol (8 mL), tetrahydrofuran (4 mL),and 50% aqueous NaOH (2 mL) was heated to 50° C. for approximately 2 hr(additional ethanol and THF can be added if the solid is not completelysoluble after 1 hr at 50° C.). The residue was neutralized to a pH of5-6 with aqueous HCl. The aqueous layer was concentrated in vacuo, andthe resulting solid was washed with acetonitrile and water, and driedunder high vacuum. A solution of the acid, NMM (3 eq), EDC (1.4 eq), andHOBT (1.5 eq) in DMF (5 mL) was heated at 40° C. for 2 hr. The amine wasadded, and then stirred at room temperature for 18-48 hr. The reactionmixture was quenched with saturated aqueous NH₄ ⁺Cl⁻, and extracted withdichloromethane. The combined organic layer was concentrated. The THPamide was purified over SiO₂ using CH₂Cl₂/methanol/triethylamine (theTHP amide may alternatively be purified by reverse-phasechromatography). The resulting solid was then dissolved in 10 mL of 4MHCl and 10 mL of methanol, and stirred at room temperature untilcompletion (30 min to 120 min). The mixture was then blown down, and theresulting solid was re-dissolved in methanol and poured into isopropylalcohol. The solid was collected and dried. THEO M+H=584.2794; observedHI RES M+H=584.2795.

Examples 125-387

[0379] The following compounds were prepared in a manner similar to thatused in the preceding examples. In the tables that follow, a genericstructure is shown above the table with substituent groups beingillustrated in the table along with available mass spectral data.

Example R K MS (ES) m/z 125

126

127

128

129

130

131

132

133

516 134

135

136

600 137

530 138

636 139

596 140

—H 502 141

579 142

542 143

614 144

585 145

549 146

—H 574 147

564 148

616 149

598 151

540.2160 152

524.225 153

544.1673 154

524.2218 155

540.2155 156

560.2387 157

555.2666 158

540.2548 159

554.2698 160

562.2378 161

541.2488 162

163

593.2131 164

578.1976 165

592.2151 166

600.1865 167

579.1984 168

543.2647 169

528.2550 170

542.2700 171

550.2390 172

529.2505 173

539.2338 174

567.2653 175

560.2249 176

544.2489 177

559.2616 178

587.2933 179

580.2504 180

546.1840 181

569.2797 182

542.2349 183

578.1288 184

607.2381 185

573.1654 186

564.1965 187

576.2552 188

556.2506 189

568.2862 190

590 191

602.2935 192

584.1298 193

534.1860 194

530.2332 195

196

580.2848 197

594.3011 198

608.3148 199

608.3152 200

582.2997 201

598.296 202

612.3124 203

626.3276 204

626.3268 205

600.3107 206

580.1822 207

546.1850 208

514.2382 210

540.2539 211

578.2106 212

558.2667 213

546.1847 214

560.2012 215

570.2608 216

584.2755 217

598.2953 218

586 219

598.1441 220

578.1966 221

548.1988 222

528.2543 223

593.2431 224

578.2359 225

564.2202 226

614.3261 227

614.2932 228

656.3399 229

230

614.3273 231

602.2901 232

568.2876 233

570.2970 234

584.3166 235

572.2787 236

584.3161 237

596.3014 238

560.2437 239

614.2883 240

629.3014 242

243

622.2636 244

616.3040 245

602.2876 246

600.3109 247

586.2949 248

572.2778 249

570.3007 250

606.2664 252

580.2147 253

587.2914 254

554.5692 256

541.1650 257

574.2388 258

543.2291 259

500.2019 260

514.2376 261

516.1723 262

518.2130 263

514.2194 264

518.2432 265

514.2375 266

530.1880 267

532.2307 268

528.2557 269

516.2557 270

518.1880 271

536.1979 272

498.2450 273

512.2615 274

532.2061

[0380]

Ex- am- ple R K MS (ES) m/z 275

578.2068 276

594.2005 277

578.2053

[0381]

Example R MS (ES) m/z 278

463.1704 279

499.2304 280

281

495.4984 282

479.1416 283

572.2800 284

539.2017 285

489.2049 286

477 287

515 288

483.1992 289

503 290

487 291

487 292

491 293

503 294

473 295

509 296

557 297

557 298

541 299

491 300

541 301

501 302

509 303

501 304

501 305

517 306

521 307

505 308

501 309

559 310

311

499 312

499 313

515 314

529 315

516 316

517 317

318

517 319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

341

342

343

344

345

346

437

348

349

350

351

352

353

354

355

356

357

358

359

360

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375

581 376

545.2320 377

529.2383 378

551.0854 379

555.252 380

569.2687 381

569.2676 382

543.2524 383

384

530.2315 385

556.2482 386

387

Example 388 In Vitro Metalloprotease Inhibition

[0382] Several hydroxamates and salts thereof were assayed for MMPactivity by an in vitro assay generally following the proceduresoutlined et al., FEBS Lett., 296(3), 263 (1992).

[0383] Recombinant human MMP-1, MMP-2, MMP-9, MMP-13, and were used inthis assay. These enzymes were prepared in the Assignee's es followingusual laboratory procedures. Specifics for preparing and e enzymes canbe found in the scientific literature describing these See, e.g., EnzymeNomenclature (Academic Press, San Diego, Calif., d the citationstherein). See also, Frije et al., J Biol. Chem., 26(24), (1994).

[0384] The MMP-1 was obtained from MMP-1 expressing transfected HT-1080cells provided by Dr. Harold Welgus of Washington University in St.Louis, Mo. The MMP-1 was activated using 4-aminophenylmercuric acetate(APMA), and then purified over a hydroxamic acid column.

[0385] The MMP-2 was obtained from MMP-2 expressing transfected cellsprovided by Dr. Gregory Goldberg of Washington University.

[0386] The MMP-9 was obtained from MMP-9 expressing transfected cellsprovided by Dr. Gregory Goldberd.

[0387] The MMP-13 was obtained as a proenzyme from a full-length cDNAclone using baculovirus, as described by V. A. Luckow, “Insect CellExpression Technology,” Protein Engineering: Principles and Practice,pp. 183-218 (edited by J. L. Cleland et al., Wiley-Liss, Inc., 1996).The expressed proenzyme was first purified over a heparin agarosecolumn, and then over a chelating zinc chloride column. The proenzymewas then activated by APMA for use in the assay. Further details onbaculovirus expression systems may be found in, for example, Luckow etal., J. Virol., 67, 4566-79 (1993). See also, O'Reilly et al,Baculovirus Expression Vectors: A Laboratory Manual (W.H. Freeman andCo., New York, N.Y., 1992). See also, King et al., The BaculovirusExpression System: A Laboratory Guide (Chapman & Hall, London, England,1992).

[0388] The enzyme substrate was a methoxycoumarin-containing polypeptidehaving the following sequence:

[0389] MCA-ProLeuGlyLeuDpaAlaArgNH₂

[0390] Here, “MCA” is methoxycoumarin and “Dpa” is3-(2,4-dinitrophenyl)-L-2,3-diaminopropionyl alanine. This substrate iscommercially available from Baychem (Redwood City, Calif.) as productM-1895.

[0391] The subject hydroxamate (or salt thereof) was dissolved atvarious concentrations using 1% dimethyl sulfoxide (DMSO) in a buffercontaining 100 mM Tris-HCl, 100 mM NaCl, 10 mM CaCl₂, and 0.05%polyethyleneglycol (23) lauryl ether at a pH of 7.5. These solutionswere then compared to a control (which contained equal amount ofDMSO/buffer solution, but no hydroxamate compound) using Microfluor™White Plates (Dynatech, Chantilly, Va.). Specifically, The MMPs wereactivated with APMA or trypsin. Then the various hydroxamate/DMSO/buffersolutions were incubated in separate plates at room temperature with theactivated MMP and 4 um of the MMP substrate. The control likewise wasincubated at room temperature in separate plates with the MMP and 4 uMof the MMP substrate. In the absence of inhibitor activity, afluorogenic peptide was cleaved at the gly-leu peptide bond of thesubstrate, separating the highly fluorogenic peptide from a2,4-dinitrophenyl quencher, resulting in an increase of fluorescentintensity (excitation at 328 nm/emission at 415). Inhibition wasmeasured as a reduction in fluorescent intensity as a function ofinhibitor concentration using a Perkin Elmer (Norwalk, Conn.) L550 platereader. The IC₅₀'s were then calculated from these measurements. Theresults are set forth in the following Table A. Inhibition Table A (nM)Example MMP-13 MMP-2 MMP-1 Number IC₅₀(nM) IC₅₀(nM) IC₅₀(nM) 4 15.62,900 >10000 5 15.6 2,900 >10000 6 18.1 >10000 >10000 7 18.04,500 >10000 8 50.0 2,500 >10000 9 12.2 5,600 >10000 10 40.06,000 >10000 11 37.0 2,700 >10000 12 6.70 1,400 >10000 13 31.63,500 >10000 14 45.0 >10000 >10000 15 28.0 5,500 >10000 16 42.54,800 >10000 17 70.0 7,000 >10000 18 >10000 >10000 >10000 19 90.010,000 >10000 20 23.5 4,500 >10000 21 6.00 1,600 >10000 22 10.73,600 >10000 23 6.40 1,600 >10000 24 6.70 700 >10000 25 4.00 445 >1000028 10.0 800 >10000 29 20.0 4,500 >10000 30 18.1 >10000 >10000 31 15.82,100 >10000 32 30.0 1,750 >10000 33 67.4 6,000 67.4 34 19.33,700 >10000 35 26.8 900 >10000 36 70.0 5,400 >10000 3782.5 >10000 >10000 38 17.9 5,000 >10000 39 19.0 1,050 >10000 40 80.05,700 >10000 41 11.4 6,000 >10000 42 20.0 6,500 >10000 44 40.05,700 >10000 45 10.0 >10000 >10000 46 20.0 2,000 >10000 47 4.10562 >10000 48 0.2 0.3 3,000 49 2.00 59.0 >10000 50 50.0 5,000 >10000 512.20 0.45 >10000 52 32.6 900 >10000 53 27.8 7,000 >10000 58 28.8900 >10000 59 110 1,000 >10000 60 11.4 1,200 >10000 70 43.5 2,050 >1000072 80.0 10,000 >10000 73 9.00 8,300 >10000 74 76.9 10,000 >10000 754.80 >10000 >10000 76 32.7 2,700 >10000 77 160 >10000 >10000 7870.0 >10000 >10000 79 37.3 >10000 >10000 80 70.0 >10000 >10000 8119.3 >10000 >10000 82 20.0 7,300 >10000 83 90.0 >10000 >10000 84105 >10000 >10000 85 14.8 9,000 >10000 86 13.8 >10000 >10000 87130 >10000 >10000 88 19.3 9,000 >10000 89 60.0 >10000 >10000 90150 >10000 >10000 91 35.0 >10000 >10000 92 50.0 >10000 >10000 9350.0 >10000 >10000 95 100 >10000 >10000 96 63.1 >10000 >10000 9759.1 >10000 >1,000 98 50.0 >10000 >10000 99 50.0 >10000 >10000 10034.9 >10000 >10000 101 40.0 >10000 >10000 102 30.6 9,000 >10000 10337.3 >10000 >10000 104 90.0 >10000 >10000 105 175 >10000 >10000 106115 >10000 >10000 107 30.6 7,000 >10000 108 28.6 >10000 >10000 10960.0 >10000 >10000 110 40.0 >10000 >10000 111 40.0 10,000 >10000 11248.5 >10000 >10000 113 60.0 10,000 >10000 114 120 >10000 >10000 115200 >10000 >10000 116 77.0 >10000 >10000 117 65.0 >10000 >10000 118420 >10000 >10000 119 1.0 200 >10000 120 0.85 126 >10000 (an average of2 (an average of 2 experiments) experiments) 121 0.1 58.8 >10000 122 0.1106.5 123 0.1 46.3 >10000 124 0.4 56.4 >10000 126 11.1 400 127 3.0 80.0128 5.5 230 129 11.4 260 130 3.0 700 >10000 132 50.0 430 133 1.716.1 >10000 134 4.5 427 >10000 135 0.5 8.0 136 50.4 246 >10000 137 0.74.5 >10000 138 5.9 1500 >10000 139 1.8 330 >10000 140 18.1 800 >10000141 1.4 160 >10000 142 6.0 420 >10000 143 2.1 100 >10000 145 2102100 >10000 146 4.0 200 >10000 147 20.0 145 >10000 148 2.9 80.0 >10000149 16.9 210 >10000 151 1.3 127.6 >10000 152 0.6 56.3 >10000 153 0.230.6 >10000 154 2.4 176.5 >10000 155 1.4 43.8 >10000 156 0.71335.9 >10000 157 2.7 781.6 >10000 158 2.4 217.8 >10000 159 0.5 32.2 1600.4 197.5 >10000 161 0.3 234.7 162 2.7 494.6 >10000 163 3.43231.9 >10000 164 5.4 942.3 >10000 165 85.9 1754 166 438 >10000 167 4.72949 168 2.1 2181.2 >10000 169 2.6 1061.7 >10000 170 1.3 134.1 >10000171 1.9 405.4 >10000 172 3.1 649.1 173 0.9 117.3 174 1.1 1069.1 >10000175 0.7 136.6 >10000 176 0.4 122.3 >10000 177 1.4 166.8 178 3.0 1976.5179 0.7 161.3 >10000 180 0.3 52.7 >10000 181 2.3 935.7 >10000 182 1.1115.4 >10000 183 0.7 37.9 >10000 184 1.5 360.2 >10000 185 5.187.4 >10000 186 3.5 94.4 >10000 187 2.7 242.4 >10000 188 2.0249.9 >10000 189 <0.1 258 >10000 190 0.2 23.1 >10000 191 3.02286.9 >10000 192 1.3 103.3 >10000 193 0.4 98.7 >10000 194 9.11229.7 >10000 195 0.3 462.8 >10000 196 1.0 750.1 >10000 197 1.41720.1 >10000 198 12.0 2565.6 199 11.7 3390.0 >10000 200 0.51398.8 >10000 201 0.2 6315.4 >10000 202 0.4 1017.6 >10000 203 0.6 816.42367 204 0.2 1045.8 >10000 205 <0.1 411.5 >10000 206 1.8 199.4 >10000207 1.1 4.4 >10000 208 0.1 19.6 >10000 210 1.1 13.1 >10000 211 1.2122.3 >10000 212 0.2 109.7 >10000 213 0.5 25.8 >10000 214 1.7159.8 >10000 215 0.9 22.7 >10000 216 1.5 46.4 >10000 217 1.3270.0 >10000 218 0.2 75.7 >10000 219 4.9 258.2 >10000 220 1.7289.8 >10000 221 3.4 301.1 >10000 222 1.0 196.6 >10000 223 2.580.4 >10000 224 0.4 72.9 >10000 225 0.2 40.8 >10000 226 <0.1 1024 >10000227 1.4 132.1 >10000 228 19.5 154.6 229 0.2 8.5 >10000 230 0.1745.0 >10000 231 0.5 39.4 >10000 232 1.3 624.4 >10000 233 1.21046.1 >10000 234 7.5 2444.7 >10000 235 0.8 118.0 >10000 236 1.51848.4 >10000 237 2.1 1914.8 >10000 238 1.8 62.1 239 0.6 75.8 240 2.886.0 242 1.0 87.5 243 0.3 56.0 >10000 244 0.2 15.2 245 1.1 38.6 246 1.02712.9 >10000 247 0.3 111.4 >10000 248 0.6 141.0 >10000 2495.8 >10000 >10000 250 2.1 107.2 252 0.4 14.3 253 1.7 38.7 >10000 254 1.3132.0 >10000 256 7.5 35.4 257 258 14.1 45.4 259 0.4 0.6 260 0.41.2 >10000 261 0.8 1.0 262 1.0 1.7 263 1.5 2.6 >10000 264 0.8 3.1 2650.5 3.2 266 1.7 4.5 267 0.4 1.7 >10000 268 1.2 5.0 >10000 269 1.44.5 >10000 270 1.1 1.9 >10000 271 0.8 1.7 >10000 272 1.3 5.9 >10000 2732.5 13.4 274 2.1 5.2 >10000 275 183.6 6736.9 276 126.7 2733.4 277274.5 >10000 279 160 3300 >10000 280 27.1 500 >10000 281 11.4 500 >10000282 0.7 2.0 >10000 284 33.7 5400 >10000 285 35.0 3100 >10000 28770.0 >10000 >10000 288 4.4 60.7 >10000 289 6.0 160 >10000 290 0.482.0 >10000 291 0.8 160 >10000 292 3.2 35.0 >10000 293 37.3 1400 >10000294 3.1 120 >10000 295 28.6 300 >10000 296 25.1 210 >10000 297 15.8250 >10000 298 34.9 240 >10000 299 9.4 106 >10000 300 14.8 240 >10000301 37 3000 >10000 302 1.9 35 >10000 303 3.1 590 >10000 304 1.6270 >10000 305 6.0 3300 >10000 306 9.0 800 >10000 307 0.9 145 >10000 3083.0 1280 >10000 309 22.0 270 >10000 310 6.0 4500 >10000 311 3.7700 >10000 312 1.2 175 >10000 313 3.0 445 >10000 314 12.2 3700 >10000315 4.5 700 >10000 316 2.0 700 >10000 317 4.0 23.5 >10000 318 5.7130 >10000 319 4.0 175 >10000 320 2.3 10,000 >10000 321 200 1400 >10000322 140 1400 >10000 323 7.0 505 >10000 324 11.3 70.0 >10000 325 11.01750 >10000 326 3.0 70.0 >10000 327 5.0 4700 >10000 328 4.5 186 >10000329 20.0 1800 ND 330 — — ND 331 1.2 250 ND 332 1.3 120 ND 333 3.7600 >10000 334 5.5 440 ND 335 2.7 1500 >10000 336 2.0 34.9 ND 337 1.740.0 ND 338 — — ND 339 — — ND 340 16.5 10,000 >10000 341 — — ND 342 2.076.9 ND 374 5.6 970 >10000 375 34.4 2663 376 6.4 2185.4 >10000 377 0.4361.4 >10000 378 0.3 28.4 >10000 379 0.6 1266.4 >10000 380 9.72287.6 >10000 381 3.5 639.9 >10000 382 0.3 1305.4 >10000 383 36.9 382.4384 2.9 52.9 385 3.2 34.6 386 15.2 1901.1 387 4.5 344.4

Example 389 In Vivo Angiogenesis Assay

[0392] The study of angiogenesis depends on a reliable and reproduciblemodel for the stimulation and inhibition of a neovascular response. Thecorneal micropocket assay provides such a model of angiogenesis in thecornea of a mouse. See, A Model of Angiogenesis in the Mouse Cornea;Kenyon, B M, et al., Investigative Ophthalmology & Visual Science, July1996, Vol. 37, No. 8.

[0393] In this assay, uniformly sized Hydron™ pellets containing bFGFand sucralfate were prepared and surgically implanted into the stromamouse cornea adjacent to the temporal limbus. The pellets were formed bymaking a suspension of 20 μL sterile saline containing 10 μg recombinantbFGF, 10 mg of sucralfate and 10 μL of 12 percent Hydron™ in ethanol.The slurry was then deposited on a 10×10 mm piece of sterile nylon mesh.After drying, the nylon fibers of the mesh were separated to release thepellets.

[0394] The corneal pocket is made by anesthetizing a 7 week old C57Bl/6female mouse, then proptosing the eye with ajeweler's forceps. Using adissecting microscope, a central, intrastromal linear keratotomy ofapproximately 0.6 mm in length is performed with a #15 surgical blade,parallel to the insertion of the lateral rectus muscle. Using a modifiedcataract knife, a lamellar micropocket is dissected toward the temporallimbus. The pocket is extended to within 1.0 mm of the temporal limbus.A single pellet was placed on the corneal surface at the base of thepocket with a jeweler's forceps. The pellet was then advanced to thetemporal end of the pocket. Antibiotic ointment was then applied to theeye.

[0395] Mice were dosed on a daily basis for the duration of the assay.Dosing of the animals was based on bioavailability and overall potencyof the compound. an exemplary dose was 10 or 50 mg/kg (mpk) bid, po.Neovascularization of the corneal stroma begins at about day three andwas permitted to continue under the influence of the assayed compounduntil day five. At day five, the degree of angiogenic inhibition wasscored by viewing the neovascular progression with a slit lampmicroscope.

[0396] The mice were anesthetized and the studied eye was once againproptosed. The maximum vessel length of neovascularization, extendingfrom the limbal vascular plexus toward the pellet was measured. Inaddition, the contiguous circumferential zone of neovascularization wasmeasured as clock hours, where 30 degrees of arc equals one clock hour.The area of angiogenesis was calculated as follows.${area} = \frac{\left( {0.4 \times {clock}\quad {hours} \times 3.14 \times {vessel}\quad {length}\quad \left( {{in}\quad {mm}} \right)} \right)}{2}$

[0397] Five to six mice were utilized for each compound in each study.The studied mice were thereafter compared to control mice and thedifference in the area of neovascularization was recorded as an averagedvalue. Each group of mice so studied constitutes an “n” value of one, sothat “n” values greater than one represent multiple studies whoseaveraged result is provided in the table. A contemplated compoundtypically exhibits about 25 to about 75 percent inhibition, whereas thevehicle control exhibits zero percent inhibition.

Example 390 In Vivo PC-3 Tumor Reduction

[0398] PC-3 human pancreatic cancer eclls (ATCC CRL 1435) were grown to90% confluence in F12/MEM (Gibco) containing 7% FBS (Gibco). Cells weremechanically harvested using a rubber scraper, and then washed twicewith cold medium. The resulting cells were resuspended in cold mediumwith 30% matrigel (Collaborative Research) and the cell-containingmedium was maintained on ice until used.

[0399] Balb/c nu/nu mice at 7-9 weeks of age were anesthetized withavertin [2,2,2-tribromethanol/t-amyl alcohol (1 g/1 mL) diluted 1:60into phosphate-buffered sline] and 3-5×10⁶ of the above cells in 0.2 mLof medium were injected into the left flank of each mouse. Cells wereinjected in the morning, whereas dosing with an inhibitor began at 6 PM.The animals were gavaged BID from day zero (cell injection day) to day25-30, at which time the animals were euthanized and tumors weighed.

[0400] Compounds were dosed at 10 mg/mL in 0.5% methylcellulose/0.1%polysorbate 80 to provide a 50 mg/kg (mpk) dose twice each day, ordiluted to provide a 10 mg/kg (mpk) dose twice each day. Tumormeasurements began on day 7 and continued every third or fourth dayuntil completion of the study. Groups of ten mice were used in eachstudy and nine to ten survived. Each group of mice so studiedconstitutes an “n” value of one, so that “n” values greater than onerepresent multiple studies whose averaged result is provided in thetable.

Example 391 Tumor Necrosis Factor Assays

[0401] Cell Culture.

[0402] The cells used in the assay are the human moncytic line U-937(ATCC CRL-1593). The cells are grown in RPMI w/10% FCS and PSGsupplement (R-10) and are not permitted to overgrow. The assay iscarried out as follows:

[0403] 1. Count, then harvest cells by centrifugation. Resuspend thepellet in R-10 supplement to a concentration of 1.540×10⁶ cells/mL.

[0404] 2. Add test compound in 65 uL R-10 to the appropriate wells of a96-well flat bottom tissue culture plate. The initial dilution from aDMSO stock (100 mM compound) provides a 400 uM solution, from which fiveadditional three-fold serial dilutions are made. Each dilution of 65 ul(in triplicate) yields final compound test concentrations of 100 μM,33.3 μM, 11.1 μM, 3.7 μM, 1.2 μM and 0.4 μM.

[0405] 3. The counted, washed and resuspended cells (200,000 cells/well)in 130 μL are added to the wells.

[0406] 4. Incubation is for 45 min to 1 hr at 37° C. in 5% CO₂ in awater saturated container.

[0407] 5. R-10 (65 uL) containing 160 ng/mL PMA (Sigma) is added to eachwell.

[0408] 6. The test system is incubated at 37° C. in 5% CO₂ overnight(18-20 hr) under 100% humidity.

[0409] 7. Supernatant, 150 μL, is carefully removed from each well foruse in the ELISA assay.

[0410] 8. For toxicity, a 50 μL aliquot of working solution containg 5mL R-10, 5 mL MTS solution [CellTiter 96 AQueous One Solution CellProliferation Assay Cat.#G358/0,1 (Promega Biotech)] and 250 ul PMSsolution are added to each well containing the remaining supernatant andcells and the cells incubated at 37° C. in 5% CO₂ until the colordevelops. The system is excited at 570 nm and read at 630 nm.

[0411] TNF Receptor II ELISA Assay

[0412] 1. Plate 100 μL/well 2 μg/mL mouse anti-human TNFrII antibody(R&D Systems #MAB226) in 1×PBS (pH 7.1, Gibco) on NUNC-Immuno Maxisorbplate. Incubate the plate at 4° C. overnight (about 18-20 hr).

[0413] 2. Wash the plate with PBS-Tween (1×PBS w/0.05% Tween).

[0414] 3. Add 200 μL 5% BSA in PBS and block at 37° C. in a watersaturated atmosphere for 2 hr.

[0415] 4. Wash the plate with PBS-Tween.

[0416] 5. Add sample and controls (100 ul of each) to each well. Thestandards are 0, 50, 100, 200, 300 and 500 pg recombinant human TNFrII(R&D Systems #226-B2) in 100 μL 0.5% BSA in PBS. The assay is linear tobetween 400-500 pg of standard.

[0417] 6. Incubate at 37° C. in a saturated atmosphere for 1.5 hr.

[0418] 7. Wash the plate with PBS-Tween.

[0419] 8. Add 100 μL goat anti-human TNFrII polyclonal (1.5 μg/mL R&DSystems #AB226-PB in 0.5% BSA in PBS).

[0420] Incubate at 37° C. in a saturated atmosphere for 1 hr.

[0421] 10. Wash the plate with PBS-Tween.

[0422] 11. Add 100 μL anti-goat IgG-peroxidase (1:50,000 in 0.5% BSA inPBS, Sigma #A5420).

[0423] 11. Incubate at 37° C. in a saturated atmosphere for 1 hr.

[0424] 12. Wash the plate with PBS-Tween.

[0425] 13. Add 10 μL KPL TMB developer, develop at room temperature(usually about 10 min); then terminate with phosphoric acid and exciteat 450 nm and read at 570 nm.

[0426] TNFα ELISA Assay.

[0427] Coat Immulon® 2 plates with 0.1 mL/well of lug/mL Genzyme mAb in0.1 M NaHCO3 pH 8.0 buffer overnight (about 18-20 hr) at 4° C., wrappedtightly in Saran® wrap.

[0428] Flick out coating solution and block plates with 0.3 mL/wellblocking buffer overnight at 4° C., wrapped in Saran® wrap.

[0429] Wash wells thoroughly 4× with wash buffer and completely removeall wash buffer. Add 0.1 mL/well of either samples or rhTNFα standards.Dilute samples if necessary in appropriate diluant (e.g. tissue culturemedium). Dilute standard in same diluant. Standards and samples shouldbe in triplicates.

[0430] Incubate at 37° C. for 1 hr in humified container.

[0431] Wash plates as above. Add 0.1 mL/well of 1:200 dilution ofGenzyme rabbit anti-hTNFa.

[0432] Repeat incubation.

[0433] Repeat wash. Add 0.1 mL/well of 1 μg/mL Jackson goat anti-rabbitIgG (H+L)-peroxidase.

[0434] Incubate at 37° C. for 30 min.

[0435] Repeat wash. Add 0.1 mL/well of peroxide-ABTS solution.

[0436] Incubate at room temperature for 5-20 min.

[0437] Read OD at 405 nm.

[0438] 12 Reagents are:

[0439] Genzyme mouse anti-human TNF? monoclonal (Cat.# 80-3399-01)

[0440] Genzyme rabbit anti-human TNF? polyclonal (Cat.#IP-300)

[0441] Genzyme recombinant human TNF? (Cat.#TNF-H).

[0442] Jackson Immunoresearch peroxide-conjugated goat anti-rabbit IgG(H+L) (Cat.#111-035-144).

[0443] Kirkegaard/Perry peroxide ABTS solution (Cat#50-66-01).

[0444] Immulon 2 96-well microtiter plates.

[0445] Blocking solution is 1 mg/mL gelatin in PBS with 1× thimerasol.

[0446] Wash buffer is 0.5 mL Tween® 20 in 1 liter of PBS.

Example 392 In Vitro Aggrecanase Inhibition Assay

[0447] Assays for measuring the potency (IC₅₀) of a compound towardinhibiting aggrecanase are known in the art.

[0448] One such assay, for example, has been reported in European PatentApplication Publ. No. EP 1 081 137 A1. In that assay, primary porcinechondrocytes from articular joint cartilage are isolated by sequentialtrypsin and collagenase digestion followed by collagenase digestionovernight and are plated at 2×10⁵ cells per well into 48 well plateswith 5 μCi/ml³⁵S (1000 Ci/mmol) sulphur in type 1 collagen coatedplates. Cells are allowed to incorporate label into their proteoglycanmatrix (approximately 1 week) at 37° C. under an atmosphere of 5% CO₂.The night before initiating the assay, chondrocyte monolayers are washed2 times in DMEM/1% PSF/G and then allowed to incubate in fresh DMEM/1%FBS overnight. The next morning, chondrocytes are washed once in DMEM/1%PSF/G. The final wash is allowed to sit on the plates in the incubatorwhile making dilutions. Media and dilutions are made as described in thefollowing Table C: TABLE C control media DMEM alone IL-1 media DMEM +IL-1 (5 ng/ml) drug dilutions Make all compound stocks at 10 mM in DMSO.Make a 100 μM stock of each compound in DMEM in 96-well plate. Store infreezer overnight. The next day, perform serial dilutions in DMEM withIL-1 to 5 μM, 500 nM, and 50 nM. Aspirate final wash from wells and add50 μM of compound from above dilutions to 450 μL of IL-1 media inappropriate wells of the 48 well plates. Final compound concentrationsequal 500 nM, 50 nM, and 5 nM. All samples completed in triplicate withcontrol and IL-1 alone on each plate.

[0449] Plates are labeled and only the interior 24 wells of the plateare used. On one of the plates, several columns are designated as IL-1(no drug) and control (no IL-1, no drug). These control columns areperiodically counted to monitor 35S-proteoglycan release. Control andIL-1 media are added to wells (450/L) followed by compound (50 μL) so asto initiate the assay. Plates are incubated at 37° C. with 5% CO₂atmosphere. At 40-50% release (when CPM from IL-1 media is 4-5 timescontrol media) as assessed by liquid scintillation counting (LSC) ofmedia samples, the assay is terminated (about 9 to about 12 hours).Media is removed from all wells and placed into scintillation tubes.Scintillate is added and radioactive counts are acquired (LSC). Tosolubilize cell layers, 500 μL of papain digestion buffer (0.2 M Tris,pH 7.0, 5 mM DTT, and 1 mg/ml papain) is added to each well. Plates withdigestion solution are incubated at 60° C. overnight. The cell layer isremoved from the plates the next day and placed in scintillation tubes.Scintillate is then added, and samples counted (LSC). The percent ofreleased counts from the total present in each well is determined.Averages of the triplicates are made with control background subtractedfrom each well. The percent of compound inhibition is based on IL-1samples as 0% inhibition (100% of total counts).

[0450] Another assay for measuring aggrecanase inhibition has beenreported in WIPO Int'l Publ. No. WO 00/59874. That assay reportedly usesactive aggrecanase accumulated in media from stimulated bovine cartilage(BNC) or related cartilage sources and purified cartilage aggrecanmonomer or a fragment thereof as a substrate. Aggrecanase is generatedby stimulation of cartilage slices with interleukin-1 (IL-1), tumornecrosis factor alpha (TNF-α), or other stimuli. To accumulate BNCaggrecanase in culture media, cartilage reportedly is first depleted ofendogenous aggrecan by stimulation with 500 ng/ml human recombinant IL-βfor 6 days with media changes every 2 days. Cartilage is then stimulatedfor an additional 8 days without media change to allow accumulation ofsoluble, active aggrecanase in the culture media. To decrease theamounts of matrix metalloproteinases released into the media duringaggrecanase accumulation, agents which inhibit MMP-1, -2, -3, and -9biosynthesis are included during stimulation. This BNC conditioned mediacontaining aggrecanase activity is then used as the source ofaggrecanase for the assay. Aggrecanase enzymatic activity is detected bymonitoring production of aggrecan fragments produced exclusively bycleavage at the Glu373-Ala374 bond within the aggrecan core protein byWestern analysis using the monoclonal antibody, BC-3 (Hughes, et al.,Biochem J, 306:799-804 (1995)). This antibody reportedly recognizesaggrecan fragments with the N-terminus, 374ARGSVIL, generated uponcleavage by aggrecanase. The BC-3 antibody reportedly recognizes thisneoepitope only when it is at the N-terminus and not when it is presentinternally within aggrecan fragments or within the aggrecan proteincore. Only products produced upon cleavage by aggrecanase reportedly aredetected. Kinetic studies using this assay reportedly yield a Km of1.5+/−0.35 μM for aggrecanase. To evaluate inhibition of aggrecanase,compounds are prepared as 10 mM stocks in DMSO, water, or other solventsand diluted to appropriate concentrations in water. Drug (50/L) is addedto 50 μL of aggrecanase-containing media and 50 μL of 2 mg/ml aggrecansubstrate and brought to a final volume of 200 mL in 0.2 M Tris, pH 7.6,containing 0.4 M NaCl and 40 mM CaCl₂. The assay is run for 4 hr at 37°C., quenched with 20 mM EDTA, and analyzed for aggrecanase-generatedproducts. A sample containing enzyme and substrate without drug isincluded as a positive control and enzyme incubated in the absence ofsubstrate serves as a measure of background. Removal of theglycosaminoglycan side chains from aggrecan reportedly is necessary forthe BC-3 antibody to recognize the ARGSVIL epitope on the core protein.Therefore, for analysis of aggrecan fragments generated by cleavage atthe Glu373-Ala374 site, proteoglycans and proteoglycan fragments areenzymatically deglycosylated with chondroitinase ABC (0.1 units/110 gGAG) for 2 hr at 37° C. and then with keratanase (0.1 units/110 g GAG)and keratanase II (0.002 units/10 g GAG) for 2 hr at 37° C. in buffercontaining 50 mM sodium acetate, 0.1 M Tris/HCl, pH 6.5. Afterdigestion, aggrecan in the samples is precipitated with 5 volumes ofacetone and resuspended in 30 μL of Tris glycine SDS sample buffer(Novex) containing 2.5% beta mercaptoethanol. Samples are loaded andthen separated by SDS-PAGE under reducing conditions with 4-12% gradientgels, transferred to nitrocellulose and immunolocated with 1:500dilution of antibody BC3. Subsequently, membranes are incubated with a1:5000 dilution of goat anti-mouse IgG alkaline phosphatase secondantibody and aggrecan catabolites visualized by incubation withappropriate substrate for 10-30 minutes to achieve optimal colordevelopment. Blots are quantitated by scanning densitometry andinhibition of aggrecanase determined by comparing the amount of productproduced in the presence versus absence of compound.

[0451] The above detailed description of preferred embodiments isintended only to acquaint others skilled in the art with the invention,its principles, and its practical application so that others skilled inthe art may adapt and apply the invention in its numerous forms, as theymay be best suited to the requirements of a particular use. Thisinvention, therefore, is not limited to the above embodiments, and maybe variously modified.

1. A compound or a salt thereof, wherein: the compound corresponds instructure to the Formula X:

E is selected from the group consisting of a bond, —C(O)—, and —S—; Y isselected from the group consisting of hydrogen, alkyl, alkoxy,haloalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, hydroxy, aryloxy,arylalkoxy, heteroaryloxy, heteroarylalkyl, perfluoroalkoxy,perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocyclyl,cycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl, wherein:the aryl, heteroaryl, arylalkyl, or heterocyclyl optionally issubstituted with up to 2 substituents independently selected from thegroup consisting of alkylcarbonyl, halo, nitro, arylalkyl, aryl, alkoxy,trifluoroalkyl, trifluoroalkoxy, and amino, wherein: the amino nitrogenoptionally is substituted with up to 2 substituents independentlyselected from the group consisting of alkyl and arylalkyl; and R isselected from the group consisting of hydrogen, cyano, perfluoroalkyl,trifluoromethoxy, trifluoromethylthio, haloalkyl, trifluoromethylalkyl,arylalkoxycarbonyl, aryloxycarbonyl, hydroxy, halo, alkyl, alkoxy,nitro, thiol, hydroxycarbonyl, aryloxy, arylthio, arylalkyl, aryl,arylcarbonylamino, heteroaryloxy, heteroarylthio, heteroarylalkyl,cycloalkyl, heterocylyloxy, heterocylylthio, heterocylylamino,cycloalkyloxy, cycloalkylthio, heteroarylalkoxy, heteroarylalkylthio,arylalkoxy, arylalkylthio, arylalkylamino, heterocylyl, heteroaryl,arylazo, hydroxycarbonylalkoxy, alkoxycarbonylalkoxy, alkylcarbonyl,arylcarbonyl, arylalkylcarbonyl, alkylcarbonyloxy, arylalkylcarbonyloxy,hydroxyalkyl, hydroxyalkoxy, alkylthio, alkoxyalkylthio, alkoxycarbonyl,aryloxyalkoxyaryl, arylthioalkylthioaryl, aryloxyalkylthioaryl,arylthioalkoxyaryl, hydroxycarbonylalkoxy, hydroxycarbonylalkylthio,alkoxycarbonylalkoxy, alkoxycarbonylalkylthio, amino, aminocarbonyl, andaminoalkyl, wherein: the amino nitrogen optionally is substituted with:up two substituents that are independently selected from the groupconsisting of alkyl, aryl, heteroaryl, arylalkyl, cycloalkyl,arylalkoxycarbonyl, alkoxycarbonyl, arylcarbonyl, arylalkylcarbonyl,heteroarylcarbonyl, heteroarylalkylcarbonyl, and alkylcarbonyl, or twosubstituents such that the two substituents, together with the aminonitrogen, form a 5- to 8-member heterocyclyl or heteroaryl ring that:contains from zero to two additional heteroatoms that are independentlyselected from the group consisting of nitrogen, oxygen, and sulfur,optionally is substituted with up to two substituents independentlyselected from the group consisting of aryl, alkyl, heteroaryl,arylalkyl, heteroarylalkyl, hydroxy, alkoxy, alkylcarbonyl, cycloalkyl,heterocylylalkyl, alkoxycarbonyl, hydroxyalkyl, trifluoromethyl,benzofused heterocylylalkyl, hydroxyalkoxyalkyl, arylalkoxycarbonyl,hydroxycarbonyl, aryloxycarbonyl, benzofused heterocylylalkoxy,benzofused cycloalkylcarbonyl, heterocyclylalkylcarbonyl, andcycloalkylcarbonyl, the aminocarbonyl nitrogen is: unsubstituted, thereacted amine of an amino acid, substituted with one or two substituentsindependently selected from the group consisting of alkyl, hydroxyalkyl,hydroxyheteroarylalkyl, cycloalkyl, arylalkyl, trifluoromethylalkyl,heterocylylalkyl, benzofused heterocylylalkyl, benzofused cycloalkyl,and N,N-dialkylsubstituted alkylamino-alkyl, or substituted with twosubstituents such that the two substituents, together with theaminocarbonyl nitrogen, form a 5- to 8-member heterocyclyl or heteroarylring that optionally is substituted with up to two substituentsindependently selected from the group consisting of alkyl,alkoxycarbonyl, nitro, heterocylylalkyl, hydroxy, hydroxycarbonyl, aryl,arylalkyl, heteroaralkyl, and amino, wherein the amino nitrogenoptionally is substituted with: two substituents independently selectedfrom the group consisting of alkyl, aryl, and heteroaryl; or twosubstituents such that the two substituents, together with the aminonitrogen, form a 5- to 8-member heterocyclyl or heteroaryl ring, and theaminoalkyl nitrogen optionally is substituted with: up to twosubstituents independently selected from the group consisting of alkyl,aryl, arylalkyl, cycloalkyl, arylalkoxycarbonyl, alkoxycarbonyl, andalkylcarbonyl, or two substituents such that the two substituents,together with the aminoalkyl nitrogen, form a 5- to 8-memberheterocyclyl or heteroaryl ring.
 2. A compound or salt according toclaim 1, wherein R is halo.
 3. A compound or salt according to claim 1,wherein the compound corresponds in structure to Formula XA:


4. A compound or salt according to claim 3, wherein the salt is apharmaceutically acceptable salt.
 5. A compound or salt according toclaim 3, wherein Y is selected from the group consisting of aryl,arylalkyl, cycloalkyl, heteroaryl, aryloxy, arylalkoxy, heteroaryloxy,heteroarylalkyl, heterocyclyl, and cycloalkyl, wherein: the aryl,heteroaryl, arylalkyl, or heterocyclyl optionally is substituted with upto 2 substituents independently selected from the group consisting ofalkylcarbonyl, halo, nitro, arylalkyl, aryl, alkoxy, trifluoroalkyl,trifluoroalkoxy, and amino, wherein: the amino nitrogen optionally issubstituted with up to 2 substituents independently selected from thegroup consisting of alkyl and arylalkyl.
 6. A compound or salt accordingto claim 3, wherein E is a bond.
 7. A compound or salt according toclaim 3, wherein E is —C(O)—.
 8. A compound or salt according to claim3, wherein E is —S—. 9-13 (canceled)
 14. A compound or a salt thereof,wherein: the compound corresponds in structure to Formula X:

E is selected from the group consisting of a bond, —C(O)—, and —S—; andY is selected from the group consisting of cycloalkyl,2,3-dihydroindolyl, heterocyclyl, aryl, heteroaryl, arylalkyl, andheteroarylalkyl, wherein: any such substituent optionally is substitutedwith one or more optionally substituted substituents independentlyselected from the group consisting of halogen, hydroxy, keto, alkyl,haloalkyl, hydroxyalkyl, alkenyl, alkoxy, alkylcarbonyl, haloalkoxy,alkylthio, alkoxyalkyl, alkoxycarbonylalkyl, cycloalkyl,cycloalkylalkyl, cycloalkyloxy, cycloalkylalkoxy, cycloalkylalkoxyalkyl,aryl, arylalkyl, arylalkoxy, heterocyclyl, heterocyclylalkyl,heteroaryl, heteroarylcarbonyl, heterocyclylcarbonylalkyl,alkylsulfonyl, amino, aminoalkyl, and aminocarbonyl, wherein: any suchsubstituent optionally is substituted with one or more substituentsindependently selected from the group consisting of halogen, nitro,alkyl, haloalkyl, alkoxy, haloalkoxy, and alkylcarbonyl, and thenitrogen of the amino, aminoalkyl, or aminocarbonyl optionally issubstituted with up to two substituents independently selected from thegroup consisting of alkyl and cycloalkylalkyl; and R is selected fromthe group consisting of hydrogen and halogen.
 15. A compound or saltaccording to claim 14, wherein the compound corresponds in structure toFormula XA:

16-25 (canceled).
 26. A compound or salt according to claim 15, whereinE is —C(O)—. 27-28 (canceled).
 29. A compound or salt according to claim26, wherein: Y is selected from the group consisting of heterocyclyl,aryl, heteroaryl, and arylmethyl, wherein: any such substituentoptionally is substituted with one or more substituents independentlyselected from the group consisting of halogen, hydroxy, C₁-C₆-alkyl,halo-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, C₂-C₆-alkenyl, C₁-C₆-alkoxy,C₁-C₆-alkylcarbonyl, halo-C₁-C₆-alkoxy, C₁-C₆-alkylthio,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxycarbonyl-C₁-C₆-alkyl,C₃-C₆-cycloalkyl, aryl, aryl-C₁-C₆-alkyl, aryl-C₁-C₆-alkoxy,heterocyclyl, heterocyclyl-C₁-C₆-alkyl, heteroaryl, heteroarylcarbonyl,heterocyclylcarbonyl-C₁-C₆-alkyl, amino, and amino-C₁-C₆-alkyl, wherein:any such substituent optionally is substituted with one or moresubstituents independently selected from the group consisting ofhalogen, nitro, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, C₁-C₆-alkoxy, andC₁-C₆-alkylcarbonyl, and the nitrogen of the amino or amino-C₁-C₆-alkyloptionally is substituted with up to two substituents independentlyselected from the group consisting of C₁-C₆-alkyl andC₃-C₆-cycloalkyl-C₁-C₆-alkyl.
 30. A compound or salt according to claim29, wherein Y is phenyl optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, hydroxy, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl,C₂-C₆-alkenyl, C₁-C₆-alkoxy, C₁-C₆-alkylcarbonyl, halo-C₁-C₆-alkoxy,C₁-C₆-alkylthio, C₁-C₆-alkoxy-C₁-C₆-alkyl,C₁-C₆-alkoxycarbonyl-C₁-C₆-alkyl, C₃-C₆-cycloalkyl, aryl,aryl-C₁-C₆-alkyl, aryl-C₁-C₆-alkoxy, heterocyclyl,heterocyclyl-C₁-C₆-alkyl, heteroaryl, heteroarylcarbonyl,heterocyclylcarbonyl-C₁-C₆-alkyl, amino, and amino-C₁-C₆-alkyl, wherein:any such substituent optionally is substituted with one or moresubstituents independently selected from the group consisting ofhalogen, nitro, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, C₁-C₆-alkoxy, andC₁-C₆-alkylcarbonyl, and the nitrogen of the amino or amino-C₁-C₆-alkyloptionally is substituted with up to two substituents independentlyselected from the group consisting of C₁-C₆-alkyl andC₃-C₆-cycloalkyl-C₁-C₆-alkyl.
 31. A compound or salt according to claim29, wherein Y is thienyl optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, hydroxy, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl,C₂-C₆-alkenyl, C₁-C₆-alkoxy, C₁-C₆-alkylcarbonyl, halo-C₁-C₆-alkoxy,C₁-C₆-alkylthio, C₁-C₆-alkoxy-C₁-C₆-alkyl,C₁-C₆-alkoxycarbonyl-C₁-C₆-alkyl, C₃-C₆-cycloalkyl, aryl,aryl-C₁-C₆-alkyl, aryl-C₁-C₆-alkoxy, heterocyclyl,heterocyclyl-C₁-C₆-alkyl, heteroaryl, heteroarylcarbonyl,heterocyclylcarbonyl-C₁-C₆-alkyl, amino, and amino-C₁-C₆-alkyl, wherein:any such substituent optionally is substituted with one or moresubstituents independently selected from the group consisting ofhalogen, nitro, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, C₁-C₆-alkoxy, andC₁-C₆-alkylcarbonyl, and the nitrogen of the amino or amino-C₁-C₆-alkyloptionally is substituted with up to two substituents independentlyselected from the group consisting of C₁-C₆-alkyl andC₃-C₆-cycloalkyl-C₁-C₆-alkyl. 32-33 (canceled).
 34. A compound or saltaccording to claim 26, wherein: Y is selected from the group consistingof aryl, heteroaryl, arylmethyl, and heteroarylmethyl, wherein: any suchsubstituent optionally is substituted with one or more substituentsindependently selected from the group consisting of halogen,C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, C₂-C₆-alkenyl, C₁-C₆-alkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₃-C₆-cycloalkyl-C₁-C₆-alkyl,C₃-C₆-cycloalkyloxy, C₃-C₆-cycloalkyl-C₁-C₆-alkoxy,C₃-C₆-cycloalkyl-C₁-C₆-alkoxy-C₁-C₆-alkyl, heterocyclyl-C₁-C₆-alkyl,amino, and amino-C₁-C₆-alkyl, wherein: the nitrogen of the amino oramino-C₁-C₆-alkyl optionally is substituted with up to two substituentsindependently selected from the group consisting of C₁-C₆-alkyl.
 35. Acompound or salt according to claim 34, wherein Y is phenyl orphenylmethyl, wherein: the phenyl or phenylmethyl optionally issubstituted with one or more substituents independently selected fromthe group consisting of halogen, C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl,C₂-C₆-alkenyl, C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl,C₃-C₆-cycloalkyl-C₁-C₆-alkyl, C₃-C₆-cycloalkyloxy,C₃-C₆-cycloalkyl-C₁-C₆-alkoxy,C₃-C₆-cycloalkyl-C₁-C₆-alkoxy-C₁-C₆-alkyl, heterocyclyl-C₁-C₆-alkyl,amino, and amino-C₁-C₆-alkyl, wherein: the nitrogen of the amino oramino-C₁-C₆-alkyl optionally is substituted with up to two substituentsindependently selected from the group consisting of C₁-C₆-alkyl. 36-40(canceled).
 41. A compound or salt according to claim 34, wherein Y isthienyl or thienylmethyl, wherein: the thienyl or thienylmethyloptionally is substituted with one or more substituents independentlyselected from the group consisting of halogen, C₁-C₆-alkyl,hydroxy-C₁-C₆-alkyl, C₂-C₆-alkenyl, C₁-C₆-alkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₃-C₆-cycloalkyl-C₁-C₆-alkyl,C₃-C₆-cycloalkyloxy, C₃-C₆-cycloalkyl-C₁-C₆-alkoxy,C₃-C₆-cycloalkyl-C₁-C₆-alkoxy-C₁-C₆-alkyl, heterocyclyl-C₁-C₆-alkyl,amino, and amino-C₁-C₆-alkyl, wherein: the nitrogen of the amino oramino-C₁-C₆-alkyl optionally is substituted with up to two substituentsindependently selected from the group consisting of C₁-C₆-alkyl. 42-46(canceled).
 47. A compound or salt according to claim 15, wherein E is abond. 48-49 (canceled).
 50. A compound or salt according to claim 47,wherein: Y is selected from the group consisting of aryl,2,3-dihydroindolyl, heterocyclyl, and heteroaryl, wherein: any suchsubstituent optionally is substituted with one or more substituentsindependently selected from the group consisting of halogen, keto,hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy, halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy,aryl, aminocarbonyl, and C₁-C₆-alkylsulfonyl, wherein: any suchsubstituent optionally is substituted with one or more substituentsindependently selected from the group consisting of halogen,halo-C₁-C₆-alkyl, and halo-C₁-C₆-alkoxy, and the nitrogen of theaminocarbonyl optionally is substituted with up to 2 substituentsindependently selected from the group consisting of C₁-C₆-alkyl.
 51. Acompound or salt according to claim 50, wherein Y is phenyl optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, keto, hydroxy, C₁-C₆-alkyl,C₁-C₆-alkoxy, halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy, aryl, aminocarbonyl,and C₁-C₆-alkylsulfonyl, wherein: any such substituent optionally issubstituted with one or more substituents independently selected fromthe group consisting of halogen, halo-C₁-C₆-alkyl, andhalo-C₁-C₆-alkoxy, and the nitrogen of the aminocarbonyl optionally issubstituted with up to 2 substituents independently selected from thegroup consisting of C₁-C₆-alkyl.
 52. A compound or salt according toclaim 47, wherein: Y is selected from the group consisting ofheteroaryl, aryl, and heterocyclyl, wherein: any such substituentoptionally is substituted with one or more substituents independentlyselected from the group consisting of halogen, C₁-C₆-alkyl,C₁-C₆-alkoxy, and aryl, wherein: the aryl optionally is substituted withone or more substituents independently selected from the groupconsisting of halo-C₁-C₆-alkyl.
 53. A compound or salt according toclaim 50, wherein Y is phenyl optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, C₁-C₆-alkyl, C₁-C₆-alkoxy, and aryl, wherein: the aryloptionally is substituted with one or more substituents independentlyselected from the group consisting of halo-C₁-C₆-alkyl.
 54. A compoundor salt according to claim 15, wherein E is —S—. 55-56 (canceled).
 57. Acompound or salt according to claim 54, wherein: Y is selected from thegroup consisting of cycloalkyl, aryl, arylmethyl, and heteroaryl,wherein: any such substituent optionally is substituted with one or moresubstituents independently selected from the group consisting ofhalogen, halo-C₁-C₆-alkyl, and halo-C₁-C₆-alkoxy.
 58. A compound or saltaccording to claim 54, wherein: Y is heteroaryl.
 59. A method fortreating a pathological condition in an animal, wherein: the methodcomprises administering a compound recited in claim 1 (or apharmaceutically acceptable salt thereof) to the animal in an amounteffective to treat the condition; the condition is treatable byinhibiting matrix metalloprotease activity; and the condition isselected from the group consisting of tissue destruction, a fibroticdisease, matrix weakening, defective injury repair, a cardiovasculardisease, a pulmonary disease, a kidney disease, and a central nervoussystem disease.
 60. A method according to claim 59, wherein the compoundcorresponds in structure to Formula XA:


61. A method according to claim 59, wherein the condition is selectedfrom the group consisting of osteoarthritis, rheumatoid arthritis,septic arthritis, tumor invasion, tumor metastasis, tumor angiogenesis,a decubitis ulcer, a gastric ulcer, a corneal ulcer, periodontaldisease, liver cirrhosis, fibrotic lung disease, otosclerosis,atherosclerosis, multiple sclerosis, dilated cardiomyopathy,epidermolysis bullosa, aortic aneurysm, weak injury repair, an adhesion,scarring, congestive heart failure, coronary thrombosis, emphysema,proteinuria, and Alzheimer's disease.
 62. A method according to claim59, wherein the condition is selected from the group consisting ofrheumatoid arthritis, osteoarthritis, septic arthritis, cornealulceration, epidermal ulceration, gastric ulceration, tumor metastasis,tumor invasion, tumor angiogenesis, periodontal disease, proteinuria,Alzheimer's disease, coronary thrombosis, bone disease, and defectiveinjury repair. 63 (canceled).
 64. A method for treating a pathologicalcondition in an animal, wherein: the condition is treatable byinhibiting matrix metalloprotease-2, matrix metalloprotease-9, and/ormatrix metalloprotease-13 activity; and the method comprisingadministering a compound recited in claim 1 (or apharmaceutically-acceptable salt thereof) to the animal in an amounteffective to inhibit matrix metalloprotease-2, matrix metalloprotease-9,and/or matrix metalloprotease-13.
 65. A method according to claim 64,wherein the compound corresponds in structure to Formula XA:


66. A method according to claim 64, wherein the compound inhibits matrixmetalloprotease-13 selectively over both matrix metalloprotease-1 andmatrix metalloprotease-14. 67-68 (canceled).
 69. A method for treating apathological condition in an animal, wherein: the method comprisesadministering a compound recited in claim 1 (or apharmaceutically-acceptable salt thereof) to the animal in an amounteffective to or treat the condition, and the condition is treatable byinhibiting with TNF-α convertase activity. 70-71 (canceled).
 72. Amethod for treating a pathological condition in an animal, wherein: thecondition is treatable by inhibiting aggrecanase activity; and themethod comprises administering a compound of claim 1 (or apharmaceutically-acceptable salt thereof) to the animal in an amounteffective to or treat the condition.
 73. A method according to claim 72,wherein the compound corresponds in structure to Formula XA:

74-78 (canceled).
 79. A method for treating a pathological condition inan animal, wherein: the method comprises administering a compoundrecited in claim 14 (or a pharmaceutically acceptable salt thereof) tothe animal in an amount effective to treat the condition; the conditionis treatable by inhibiting matrix metalloprotease activity; and thecondition is selected from the group consisting of tissue destruction, afibrotic disease, matrix weakening, defective injury repair, acardiovascular disease, a pulmonary disease, a kidney disease, and acentral nervous system disease.
 80. A method according to claim 79,wherein the compound corresponds in structure to Formula XA:


81. A method according to claim 79, wherein Y is selected from the groupconsisting of heterocyclyl, aryl, heteroaryl, and arylmethyl, wherein:any such substituent optionally is substituted with one or moresubstituents independently selected from the group consisting ofhalogen, hydroxy, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl,C₂-C₆-alkenyl, C₁-C₆-alkoxy, C₁-C₆-alkylcarbonyl, halo-C₁-C₆-alkoxy,C₁-C₆-alkylthio, C₁-C₆-alkoxy-C₁-C₆-alkyl,C₁-C₆-alkoxycarbonyl-C₁-C₆-alkyl, C₃-C₆-cycloalkyl, aryl,aryl-C₁-C₆-alkyl, aryl-C₁-C₆-alkoxy, heterocyclyl,heterocyclyl-C₁-C₆-alkyl, heteroaryl, heteroarylcarbonyl,heterocyclylcarbonyl-C₁-C₆-alkyl, amino, and amino-C₁-C₆-alkyl, wherein:any such substituent optionally is substituted with one or moresubstituents independently selected from the group consisting ofhalogen, nitro, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, C₁-C₆-alkoxy, andC₁-C₆-alkylcarbonyl, and the nitrogen of the amino or amino-C₁-C₆-alkyloptionally is substituted with up to two substituents independentlyselected from the group consisting of C₁-C₆-alkyl andC₃-C₆-cycloalkyl-C₁-C₆-alkyl.
 82. A method according to claim 79,wherein Y is selected from the group consisting of aryl, heteroaryl,arylmethyl, and heteroarylmethyl, wherein: any such substituentoptionally is substituted with one or more substituents independentlyselected from the group consisting of halogen, C₁-C₆-alkyl,hydroxy-C₁-C₆-alkyl, C₂-C₆-alkenyl, C₁-C₆-alkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₃-C₆-cycloalkyl-C₁-C₆-alkyl,C₃-C₆-cycloalkyloxy, C₃-C₆-cycloalkyl-C₁-C₆-alkoxy,C₃-C₆-cycloalkyl-C₁-C₆-alkoxy-C₁-C₆-alkyl, heterocyclyl-C₁-C₆-alkyl,amino, and amino-C₁-C₆-alkyl, wherein: the nitrogen of the amino oramino-C₁-C₆-alkyl optionally is substituted with up to two substituentsindependently selected from the group consisting of C₁-C₆-alkyl.
 83. Amethod according to claim 79, wherein the condition is selected from thegroup consisting of osteoarthritis, rheumatoid arthritis, septicarthritis, tumor invasion, tumor metastasis, tumor angiogenesis, adecubitis ulcer, a gastric ulcer, a corneal ulcer, periodontal disease,liver cirrhosis, fibrotic lung disease, otosclerosis, atherosclerosis,multiple sclerosis, dilated cardiomyopathy, epidermolysis bullosa,aortic aneurysm, weak injury repair, an adhesion, scarring, congestiveheart failure, coronary thrombosis, emphysema, proteinuria, andAlzheimer's disease.
 84. A method for treating a pathological conditionin an animal, wherein: the condition is treatable by inhibiting matrixmetalloprotease-2, matrix metalloprotease-9, and/or matrixmetalloprotease-13 activity; and the method comprising administering acompound recited in claim 14 (or a pharmaceutically-acceptable saltthereof) to the animal in an amount effective to inhibit matrixmetalloprotease-2, matrix metalloprotease-9, and/or matrixmetalloprotease-13.
 85. A method according to claim 84, herein thecompound corresponds in structure to Formula XA:


86. A method according to claim 84, wherein Y is selected from the groupconsisting of heterocyclyl, aryl, heteroaryl, and arylmethyl, wherein:any such substituent optionally is substituted with one or moresubstituents independently selected from the group consisting ofhalogen, hydroxy, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl,C₂-C₆-alkenyl, C₁-C₆-alkoxy, C₁-C₆-alkylcarbonyl, halo-C₁-C₆-alkoxy,C₁-C₆-alkylthio, C₁-C₆-alkoxy-C₁-C₆-alkyl,C₁-C₆-alkoxycarbonyl-C₁-C₆-alkyl, C₃-C₆-cycloalkyl, aryl,aryl-C₁-C₆-alkyl, aryl-C₁-C₆-alkoxy, heterocyclyl,heterocyclyl-C₁-C₆-alkyl, heteroaryl, heteroarylcarbonyl,heterocyclylcarbonyl-C₁-C₆-alkyl, amino, and amino-C₁-C₆-alkyl, wherein:any such substituent optionally is substituted with one or moresubstituents independently selected from the group consisting ofhalogen, nitro, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, C₁-C₆-alkoxy, andC₁-C₆-alkylcarbonyl, and the nitrogen of the amino or amino-C₁-C₆-alkyloptionally is substituted with up to two substituents independentlyselected from the group consisting of C₁-C₆-alkyl andC₃-C₆-cycloalkyl-C₁-C₆-alkyl.
 87. A method according to claim 84,wherein Y is selected from the group consisting of aryl, heteroaryl,arylmethyl, and heteroarylmethyl, wherein: any such substituentoptionally is substituted with one or more substituents independentlyselected from the group consisting of halogen, C₁-C₆-alkyl,hydroxy-C₁-C₆-alkyl, C₂-C₆-alkenyl, C₁-C₆-alkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₃-C₆-cycloalkyl-C₁-C₆-alkyl,C₃-C₆-Cycloalkyloxy, C₃-C₆-cycloalkyl-C₁-C₆-alkoxy,C₃-C₆-cycloalkyl-C₁-C₆-alkoxy-C₁-C₆-alkyl, heterocyclyl-C₁-C₆-alkyl,amino, and amino-C₁-C₆-alkyl, wherein: the nitrogen of the amino oramino-C₁-C₆-alkyl optionally is substituted with up to two substituentsindependently selected from the group consisting of C₁-C₆-alkyl.
 88. Amethod according to claim 84, wherein the compound inhibits matrixmetalloprotease-13 selectively over both matrix metalloprotease-1 andmatrix metalloprotease-14. 89-90 (canceled).
 91. A method for treating apathological condition in an animal, wherein: the method comprisesadministering a compound recited in claim 14 (or apharmaceutically-acceptable salt thereof) to the animal in an amounteffective to treat the condition, and the condition is treatable byinhibiting TNF-α convertase activity. 92-95 (canceled).
 96. A method fortreating a pathological condition in an animal, wherein: the conditionis treatable by inhibiting aggrecanase activity; and the methodcomprises administering a compound of claim 14 (or apharmaceutically-acceptable salt thereof) to the animal in an amounteffective to treat the condition.
 97. A method according to claim 96,herein the compound corresponds in structure to Formula XA:


98. A method according to claim 96, wherein Y is selected from the groupconsisting of heterocyclyl, aryl, heteroaryl, and arylmethyl, wherein:any such substituent optionally is substituted with one or moresubstituents independently selected from the group consisting ofhalogen, hydroxy, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl,C₂-C₆-alkenyl, C₁-C₆-alkoxy, C₁-C₆-alkylcarbonyl, halo-C₁-C₆-alkoxy,C₁-C₆-alkylthio, C₁-C₆-alkoxy-C₁-C₆-alkyl,C₁-C₆-alkoxycarbonyl-C₁-C₆-alkyl, C₃-C₆-cycloalkyl, aryl,aryl-C₁-C₆-alkyl, aryl-C₁-C₆-alkoxy, heterocyclyl,heterocyclyl-C₁-C₆-alkyl, heteroaryl, heteroarylcarbonyl,heterocyclylcarbonyl-C₁-C₆-alkyl, amino, and amino-C₁-C₆-alkyl, wherein:any such substituent optionally is substituted with one or moresubstituents independently selected from the group consisting ofhalogen, nitro, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, C₁-C₆-alkoxy, andC₁-C₆-alkylcarbonyl, and the nitrogen of the amino or amino-C₁-C₆-alkyloptionally is substituted with up to two substituents independentlyselected from the group consisting of C₁-C₆-alkyl andC₃-C₆-cycloalkyl-C₁-C₆-alkyl.
 99. A method according to claim 96,wherein Y is selected from the group consisting of aryl, heteroaryl,arylmethyl, and heteroarylmethyl, wherein: any such substituentoptionally is substituted with one or more substituents independentlyselected from the group consisting of halogen, C₁-C₆-alkyl,hydroxy-C₁-C₆-alkyl, C₂-C₆-alkenyl, C₁-C₆-alkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₃-C₆-cycloalkyl-C₁-C₆-alkyl,C₃-C₆-cycloalkyloxy, C₃-C₆-cycloalkyl-C₁-C₆-alkoxy,C₃-C₆-cycloalkyl-C₁-C₆-alkoxy-C₁-C₆-alkyl, heterocyclyl-C₁-C₆-alkyl,amino, and amino-C₁-C₆-alkyl, wherein: the nitrogen of the amino oramino-C₁-C₆-alkyl optionally is substituted with up to two substituentsindependently selected from the group consisting of C₁-C₆-alkyl. 100-104(canceled).
 105. A pharmaceutical composition comprising a compoundrecited in claim 1 or a pharmaceutically acceptable salt thereof.
 106. Apharmaceutical composition according to claim 105, wherein the compoundcorresponds in structure to Formula XA:


107. A pharmaceutical composition comprising a compound recited in claim14 or a pharmaceutically acceptable salt thereof.
 108. A pharmaceuticalcomposition according to claim 107, wherein the compound corresponds instructure to Formula XA:


109. A pharmaceutical composition according to claim 107, wherein Y isselected from the group consisting of heterocyclyl, aryl, heteroaryl,and arylmethyl, wherein: any such substituent optionally is substitutedwith one or more substituents independently selected from the groupconsisting of halogen, hydroxy, C₁-C₆-alkyl, halo-C₁-C₆-alkyl,hydroxy-C₁-C₆-alkyl, C₂-C₆-alkenyl, C₁-C₆-alkoxy, C₁-C₆-alkylcarbonyl,halo-C₁-C₆-alkoxy, C₁-C₆-alkylthio, C₁-C₆-alkoxy-C₁-C₆-alkyl,C₁-C₆-alkoxycarbonyl-C₁-C₆-alkyl, C₃-C₆-cycloalkyl, aryl,aryl-C₁-C₆-alkyl, aryl-C₁-C₆-alkoxy, heterocyclyl,heterocyclyl-C₁-C₆-alkyl, heteroaryl, heteroarylcarbonyl,heterocyclylcarbonyl-C₁-C₆-alkyl, amino, and amino-C₁-C₆-alkyl, wherein:any such substituent optionally is substituted with one or moresubstituents independently selected from the group consisting ofhalogen, nitro, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, C₁-C₆-alkoxy, andC₁-C₆-alkylcarbonyl, and the nitrogen of the amino or amino-C₁-C₆-alkyloptionally is substituted with up to two substituents independentlyselected from the group consisting of C₁-C₆-alkyl andC₃-C₆-cycloalkyl-C₁-C₆-alkyl.
 110. A pharmaceutical compositionaccording to claim 107, wherein Y is selected from the group consistingof aryl, heteroaryl, arylmethyl, and heteroarylmethyl, wherein: any suchsubstituent optionally is substituted with one or more substituentsindependently selected from the group consisting of halogen,C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, C₂-C₆-alkenyl, C₁-C₆-alkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₃-C₆-cycloalkyl-C₁-C₆-alkyl,C₃-C₆-cycloalkyloxy, C₃-C₆-cycloalkyl-C₁-C₆-alkoxy,C₃-C₆-cycloalkyl-C₁-C₆-alkoxy-C₁-C₆-alkyl, heterocyclyl-C₁-C₆-alkyl,amino, and amino-C₁-C₆-alkyl, wherein: the nitrogen of the amino oramino-C₁-C₆-alkyl optionally is substituted with up to two substituentsindependently selected from the group consisting of C₁-C₆-alkyl.
 111. Acompound or salt according to claim 14, wherein the compound correspondsin structure to the following formula:


112. A method according to claim 59, wherein the condition isosteoarthritis.
 113. A method according to claim 79, wherein thecondition is osteoarthritis.